Diagnostic tools in Rhinology EAACI position paper.

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Clinical and Translational
Allergy

POSITION ARTICLE AND GUIDELINES Open Access

Diagnostic tools in Rhinology EAACI position paper

Glenis Scadding 1 , Peter Hellings 2 , Isam Alobid 3 , Claus Bachert 4 , Wytske Fokkens 5 , Roy Gerth van Wijk 6 ,
Philippe Gevaert 4 , Josep Guilemany 3 , Livije Kalogjera 7 , Valerie Lund 1 , Joaquim Mullol 3 , Giovanni Passalacqua 8 ,
Elina Toskala 9 and Cornelius van Drunen 5

Abstract

This EAACI Task Force document aims at providing the readers with a comprehensive and complete overview of
the currently available tools for diagnosis of nasal and sino-nasal disease. We have tried to logically order the
different important issues related to history taking, clinical examination and additional investigative tools for
evaluation of the severity of sinonasal disease into a consensus document. A panel of European experts in the field
of Rhinology has contributed to this consensus document on Diagnostic Tools in Rhinology.

Introduction

There are several reasons for accurate investigation of
upper airways disorders like allergic rhinitis [1] and rhi-
nosinusitis [2]. The first reason relates to the fact that
such problems impact very significantly upon patients'
quality of life and that well directed treatment can ame-
liorate the impairment of quality of life. The second is
that some of these disorders are severe with significant
morbidity and even mortality, and that presentation often
occurs in the upper airway. Early diagnosis and effective
management can prevent serious consequences, like in
Wegeners' granulomatosis. The third reason relates to
the fact that upper respiratory tract problems exacerbate
lower respiratory symptoms and may extend to involve
the lower respiratory tract. The nose is an air condi-
tioner; filtering, warming and humidifying over 10,000
liters of air daily before it progresses to the lungs.

The nasal passages and associated structures bear the
brunt of environmental contact being the first site of
allergen, microbial and particle deposition. As a conse-
quence the upper airway is the location of a highly devel-
oped innate and adaptive immune system. Effective
mucociliary clearance is vital for respiratory health as evi-
denced by the effects of defects such as primary ciliary
dyskinesia (PCD) and cystic fibrosis (CF). Lower airways
disease is often preceded by nasal and sinus disease lead-
ing to a window of opportunity for early diagnosis and
possibly prevention of severe complications. For example

* Correspondence: gscadding@gmail.com

'Royal National Throat, Nose and Ear Institute, London, UK

Full list of author information is available at the end of the article

measurement of nasal nitric oxide is simple and quick
and very low levels can alert the physician to the possibi-
lity of PCD before major lung damage is sustained, thus
allowing the benefit of early physiotherapy.

Inflammatory airways diseases usually start in the nose.
This observation does not only hold true for allergic and
non-allergic rhinitis in older children and adults which
can progress to asthma, but also for respiratory occupa-
tional disease, and for rhinosinusitis which can be the pre-
sentation of Wegener's granulomatosis or Churg Strauss
syndrome and is also associated with bronchiectasis.

The ability to recognize and accurately diagnose nasal
disease should be a part of the armamentarium of all
allergists, chest physicians and paediatricians as well as
ENT surgeons. In addition, the nose provides an ideal
area for investigation of disease mechanisms. It has given
us insights into the pathogenesis of allergic disease and of
changes during pharmaco- and immunotherapy. Now
investigations into other forms of inflammatory and non-
inflammatory nose and sinus disease are ongoing with
possibly new forms of therapy as a result. So researchers
might also find this Position Paper of use. This document
aims to provide a basic introduction into methods used
in Rhinology - their applicability, specificity and sensitiv-
ity. It will hopefully become outdated soon by new
advances in the field.

History of the Patient

Rationale

The patients' history is vital in understanding and diag-
nosing the problem. In rhinitis and rhinosinusitis an

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accurate history is usually more important than any
other investigation.

The aim of any history taken is to evaluate the pre-
sence, severity and duration of symptoms, aiming at an
accurate diagnosis and enabling adequate treatment.

Definition

The medical history represents the patients' or a respon-
sible carers' account of the problem, supplemented by
direct questioning.

Technique

A one-to- one interview is preferred, with or without
the aid of a questionnaire with evaluation of the severity
of the symptoms on a Visual Analogue Scale (VAS).

In spite of the patients' history being the mainstay of
clinical diagnosis and therapeutic approach, the history
and clinical examination in allergic rhinitis may deviate
considerably from concordant SPT and slgE results [3].
Patients' history is however the primary standard used
in judging test sensitivity and specificity.
1. Allergic Rhinitis

Rhinitis is defined as having two of the listed symptoms
for >1 hour/day for >2 weeks: blockage, running (includ-
ing postnasal drip), sneezing and itching. Nasal pro-
blems are often multi-factorial in nature, which needs to
be taken into account when using the classification or
considering treatment.

The diagnosis of allergic rhinitis (AR) is based upon the
concordance between a typical history of allergic symp-
toms and diagnostic tests. Typical symptoms of AR
include rhinorrhoea, sneezing, nasal obstruction and
pruritus. Depending on the sensitization pattern, patients
with AR may be predominantly runners and sneezers or
suffer from chronic obstruction with discharge which is
mainly post nasal. Ocular symptoms are common, in par-
ticular in patients allergic to outdoor allergens. Conjunc-
tivitis is found in 70% of pollen allergic rhinitis patients
and around half of those with perennial rhinitis. Always
ask about the following eye symptoms: redness,
discharge, itching, and vision impairment. Symptoms
related to reduced smell and taste are more typical of
rhinosinusitis.

Figure 1 highlights the differences between symptoms
suggestive of AR and those usually not associated with
AR, and shows the criteria for severity of disease in rela-
tion to duration and associated extra-nasal symptoms.
History should include specific symptom-related ques-
tions like:

♦ timing of symptoms (intermittent vs persistent dis-
ease, Figure 1)

♦ severity of symptoms (mild, moderate or severe,
Figure 1)

• provoking factors e.g. animal contact

• alleviating factors e.g. holiday away from home

• occupational aggravation e.g. animal care facility

• seasonal aggravation e.g. grass pollen season

• effects of treatments tried in the past

• intolerance to medication e.g. aspirin

• associated oral allergy symptoms

Allergy is a more likely diagnosis if there is a past,
present or family history of allergic diseases (AR,
asthma, atopic dermatitis).

Rhinitis symptoms without obvious allergic triggers
may still be allergic in origin so specific IgE testing is
advisable for all sufferers. Those with a good history for
an allergic cause who are negative on specific IgE tests
in blood or on skin should have the benefit of a nasal
challenge with the likely allergen since local nasal IgE
production can occur.

AR and asthma usually co-exist, with symptoms of
rhinitis found in 75-80% of patients with asthma and
asthma in up to a third of rhinitis patients. Therefore
patients should also be asked about lower respiratory
tract symptoms (wheeze, cough, dyspnoea, sputum) and
functional measurements (spirometry, peak flow) made.

There is an association between rhinitis and OME in
childhood [4] so questions on hearing, listening, lan-
guage, learning and behavior should be included in chil-
dren with rhinitis, and ear examination and hearing
tests including tympanometry and audiometry per-
formed if a problem is suspected. Adults rarely develop
OME unless they have a severe form of rhinosinusitis
(Churg-Strauss syndrome, aspirin sensitivity, allergic
fungal sinusitis).

Pharyngitis/laryngitis- can occur secondary to rhinitis
or may be the predominant feature.

Food allergy is often associated with allergic airway
disease and atopic dermatitis [5], and should therefore
be asked for during history taking.

Sleep problems-are common in rhinitis and can be det-
rimental to quality of life and to work/school perfor-
mance. Difficulty in going to sleep, snoring, mouth
breathing at night, waking with a dry or swollen mouth
and throat, daytime somnolence, headache, ability to
attend and function at work or school should be queried.
2. Non- Allergic rhinitis

In rhinitis patients who are not allergic, i.e. having nega-
tive skin prick test results or blood analysis for allergen-
specific IgE, there is an extensive differential diagnosis
(Figure 2).

In small children frequent viral upper respiratory tract
infections occur- between 6 and 8 annually on average.
Helpful questions include whether symptoms were pre-
sent from birth (consider primary ciliary dyskinesia
(PCD) or cystic fibrosis (CF)), and whether they ever

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Symptoms suggestive
of allergic rhinitis

Symptoms usually NOT associated
with allergic rhinitis

2 or more of th« following symptoms for
> I h on most days

- watery anterior rhinorrhea

- sneezing, especially paroxysmal

- natal obstruction

- nasal pruritic
± conjunctivitis

unilateral symptom*

■ ncssl obstruction without c-her symptoms

■ mucopurulent rhinorrhea

- posterior rhinorrhea (post nasal drip)

-with thick mucous
-and/or no anterior rhinorrhea
pain

- recurrent epistaxi*

■ anosmia

Intermittent

symptoms

1 <4 aays per wee*

1 or <4 cocsecutive weeks

Persistent

symptoms

• >4 oayv'week.

• era >4 consecur »r wcoki

Mild

all of the following

• "Ormal sleep

• no irrtpo rnent of doily octvries, sport, leisure

• -o iTpoi'Tert o ; wo-k o-d school

• symptoms present but not "roubieione

X

Moderate - Severe

one or more items

• sleep disturocce

■ TDormrnl o*' do y oc'ivil es. spot*.

• impairment of vchool o' wort

• troublesome symptoms

Figure 1 Symptom-based diagnosis of allergic rhinitis

remit (if not an immune defect is possible). Serious
underlying disease is unlikely in children who are grow-
ing normally and who do not have problems beyond the
upper respiratory tract.

In adults an extensive drug history may reveal overuse
of topical alpha agonists or the possibility of aspirin or

RHINITIS

Allergic rhinitis

Infectious rhinitis

Non-allergic
non-infectious rhinitis

RHINOSINUSITIS

SUBGROUPS

Intermittent / persistent
Mild / moderate / severe
Occupational

Viral
Bacterial

Non-viral non-bacterial (Protozoa / fungi)
Drug-induced (P blokkers / vasodilators /
contraceptives / aspirin / NSAID)
Hormonal (hypothyroidism / pregnancy)
NARES (some have local IgE production)
Occupational (LMW agents / irritants)
Atrophic / rhinitis of the elderly
Idiopathic

Acute / chronic

Mild / moderate / severe

Figure 2 Differential diagnosis of rhinitis/rhinosinusitis.

NSAID hypersensitivity that usually starts in adult life.
The latter cannot be discounted if no such drug has
been safely taken in recent months and a challenge may
be necessary.

Hormonal rhinitis can occur, so questions about hor-
mone therapy, possible thyroid auto-immunity, or preg-
nancy are needed.

Atrophic rhinitis can be a primary condition attributed
to Klebsiella ozaenae or secondary to excessive surgery
or radiation.

Neurogenic rhinitis is incompletely understood but is
usually non-inflammatory, commoner in females and
less likely to be associated with asthma. It may com-
mence at a time of great stress. Old man's drip is
thought to be hormonal since it responded to testoster-
one before therapy with ipratropium bromide was found
to be effective.
3 Rhinosinusitis

Rhinitis frequently co- exists with sinusitis, so the cor-
rect term in patients with symptomatic inflammation of
the sinus cavities is rhinosinusitis.

Rhinosinusitis including nasal polyps (NP) is defined
as inflammation of the nose and the paranasal sinuses

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characterized by two or more symptoms, one of which
should be either nasal blockage/obstruction/congestion
or nasal discharge (anterior/posterior nasal drip), +/-
facial pain/pressure, +/- reduction or loss of smell; and
either endoscopic signs of polyps and/or mucopurulent
discharge primarily from middle meatus and/or;
oedema/mucosal obstruction primarily in middle mea-
tus, and/or Computerised Tomography (CT) changes
showing mucosal changes within the ostiomeatal com-
plex and/or sinuses.

The EP 3 OS document proposes to define the disease
according to the duration of symptoms:

Common cold/acute viral rhinosinusitis is defined as
an acute rhinosinusitis lasting <10 days.

Acute (non-viral or bacterial) rhinosinusitis is defined
by an increase in symptoms after 5 days or PER symp-
toms after 10 days with <12 weeks duration.

Chronic rhinosinusitis/NP is defined symptoms for
>12 weeks.

The disease can be divided into MILD, MODERATE
or SEVERE based on the total severity VAS score (0-10
cm): MILD = VAS 0-3; MODERATE = VAS 3.1-7;
SEVERE = VAS 7.1-10.

As is the case with AR, patients with rhinosinusitis
should be asked for the following:

♦ onset of symptoms (since birth, adolescence or
adulthood)

♦ timing of symptoms (acute vs chronic disease)

♦ severity of symptoms (mild, moderate or severe)

♦ provoking factors e.g. microbial or occupational
factors

♦ alleviating factors e.g. holiday away from home/
work

♦ seasonal aggravation in allergic patients

♦ effects of treatments tried in the past

♦ intolerance to medication e.g. aspirin

♦ associated bronchial symptoms

♦ familial history of sinus disease (NP disease)

Recommendations

Adequate time and attention should be given to take a
complete and accurate history both of rhinitis symptoms
and those of possible co- morbidities. The history
should suggest further diagnostic tests needed for a
proper diagnosis. All rhinitis patients should have speci-
fic IgE tests unless the history itself is diagnostic e.g.
recurrent symptoms confined to a known pollen season
with remission by avoidance.

A subgroup of patients with rhinitis symptoms need to
be referred to an ENT specialist for nasal endoscopy.
ENT referral is needed for:

- unilateral nasal problems

- nasal perforations, ulceration or collapse

- sero-sanguineous discharge

- severe crusting within the nasal cavity

- recurrent infection

- periorbital cellulitis (refer urgently)

- severe sleep problems

Quality of Life Instruments in Rhinology

Rationale

The importance of quality of life issues in nasal disease
has been well recognized. The effects of disease on daily
functioning, work, leisure and school as perceived by
the patient are considered as an important characteristic
of rhinitis severity 1 . Moreover, assessment of quality of
life is one of the standard outcome measures in clinical
trials acknowledging the fact that the classical outcome
variables may only partially characterize the disease of
the patient.

Definition

Health related quality of life has been defined as "the
functional effects of an illness and its consequent ther-
apy upon a patient, as perceived by the patient [6].
Quality of life instruments aim to describe these effects.
The patient's perspective is particularly important.

Generic and disease-specific questionnaires

In general, two types of instruments are available, gen-
eric and disease-specific questionnaires. Generic ques-
tionnaires measure physical, psychological and social
domains in all health conditions irrespective of the
underlying disease. Those questionnaires allow the com-
parison between healthy and diseased subjects. Disease-
specific instruments have been designed by asking
patients what kind of problems they experience from
their disease. Both the frequency and the importance of
impairments are measured by means of the question-
naires. These instruments have the advantage that they
describe the disease-associated problems of the patients.

There are important differences in the use of these
instruments. Specific questionnaires have better discri-
minative and evaluative properties. On the other hand
specific and generic instruments might cover different
aspects of disease [7], Moreover, an important charac-
teristic of generic instruments is the ability to measure
across diseases, thereby allowing for comparisons
between different disorders. Finally, some generic ques-
tionnaires such as the Euroqol 5D [8] have been devel-
oped for cost-effectiveness studies.

Usage of instruments
Clinical trials

Both generic and disease specific can be used in clinical
rhinitis and rhinosinusitis trials. The responsiveness to

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change seems to be better with disease specific instru-
ments. Generic instruments are less effective with mild
disease [9]. From the many generic instruments the
Short Form-36 health survey (SF-36) [10] and SF-12
[11] are commonly used in rhinitis and rhinosinusitis. In
rhinosinusitis the McGill pain questionnaire [12] and
the Glasgow benefit inventory (GBI) have been applied
in several trials. The most frequently used rhinitis speci-
fic instruments [13] are the RQLQ [14] and its varia-
tions for adults (standardized RQLQ, mini-RQLQ [15])
and other age groups and Adolescent RQLQ [16]. A ser-
ies of instruments has been developed to assess rhinosi-
nusitis. From these questionnaires the Rhinosinusitis
Disability Index (RSDI) [17] and in particular the Sino-
Nasal Outcome Test 20 (SNOT-20) [18] are the most
common outcome measures.
Cost-effectiveness studies

Cost-effectiveness studies use specific instruments
designed for this kind of analysis. The Euroqol-5D [19] is
a generic measure of health status that provides a simple
descriptive profile and a single index value that can be
used in the clinical and economic evaluation of health
care. The (RSUI) was developed as a disease specific pre-
ference-based measure of rhinitis symptoms, also to be
used in cost-effectiveness studies [20]. To date, there are
no cost-effectiveness trials in patients with rhinitis or
rhinosinusitis using these instruments. This can be attrib-
uted to a lack of cost-effectiveness studies in this area.
Clinical practice

Ideally, clinicians should be able to estimate the burden
of disease in their patients. A quality of life question-
naire might be helpful. Many HQLQ instruments how-
ever are developed for use in clinical trials. In a recent
systematic review 13 disease specific HQLQ tools for
adults were evaluated [21]. One questionnaire, the Rhi-
nasthma [22] evaluates patients with rhinitis and

asthma. Several questionnaires can be used in practice
[23-31] (see table 1).

Rhinitis control Quality of life will improve if the dis-
ease is well controlled. HRQL questionnaires, however,
do not estimate to what extent a disease is under con-
trol. In recent years new tools for asthma control have
been developed and validated. Rhinitis tools are being
developed, but not published yet.

Evidence based instruments

The development of HQLQ instruments comprises a set
of procedures for validation, determination of reliability
and responsiveness. In general, these tools are better
studied than classical outcome measures. However, in a
recent systematic review of the quality of disease specific
HQLQ four instruments only were identified as ade-
quate in terms of discriminant validity (important for
cross-sectional analysis) and responsiveness (important
for longitudinal studies). For rhinitis the RQLQ and
standardized RQLQ and for rhinosinusitis the RSOM-31
and the RhinoQOL appeared to be effective [18].

Recommendations

The choice for an instrument depends on its purpose
and the target population. For purposes of research
other questionnaires are needed than for the evaluation
of patients in clinical practice. The above-mentioned
review gives some guidance to clinicians interested in
the evaluation of quality of life in patients affected
with AR and RS [21]. It has been suggested that the
use of both generic and specific instruments may be
useful [7], although this may not be always the case.
As the outcome of quality of life assessment is only
partly associated with clinical outcome measures, it is
recommended to evaluate patients with both HRQL
and medical measures.

Table 1 Instruments used in allergic rhinitis and in chronic rhinosinusitis

Generic

Disease specific

Allergic
rhinitis

Children

Pediatric RQLQ, adolescent RQLQ

Adults

SF-36, SF-12, 15D [23], EuroQol 5D

RQLQ, standardized RQLQ, mini-RQLQ, Nocturnal Quality of Life
Questionnaire (NQLQ) [24], Rhinitis Outcome Questionnaire [25] #, Rhinitis
Symptom Utility Index (RSUI)

Chronic
rhinosinusitis

Children

(CHQ) [26]

SN-5 quality of life survey [27]

Adults

SF-36, SF-12, McGill pain questionnaire (MPQ),
EuroQol 5D, Glasgow benefit inventory (GBI)

Rhinosinusitis Outcome Measurement (RSOM-31) [18] #, Rhinosinusitis
Disability index (RSDI) #, sinonasal outcome test 16 (SNOT-16) [28] #, SNOT-
20#, Chronic sinusitis survey (CSS) [29], RhinoQol [30], Sinusitis outcomes
questionnaire (SOQ) [31]

# for use in clinical practice

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Nasal Examination

I. GENERAL INSPECTION
Rationale

In the evaluation of a patient with (sino-)nasal symptoms,
it is indispensable to start with a good inspection of the
nose and face, both during inspiration as well as during
expiration. Major anomalies can be visualized directly, like
nasal vestibulum stenosis in cleft lip patients (Figure 3),
collapse of the nostrils during inspiration (Figure 4) or
severe septal deviations. Therefore, the aim of inspection
of the nose is to delineate any anatomical problems that
can interfere with the nasal function both in rest as well as
during inspiration.
Definition

Inspection is the visual investigation of the external
structures of the nose and beyond, in order to get a first
and superficial impression of the nose and nasal
function.
Technique

During history taking and clinical examination, it is
important to look at the nasal anatomy, both at rest as
well as during inspiration. With the aid of a light source,
one can even better evaluate the bony, cartilaginous and
skin parts that constitute the nasal dorsum.
The following nasal aspects are evaluated:

- The shape: congenital or acquired abnormalities of
the ossa nasalia, middle vault and external valve area. A
widened dorsum of the nose can indicate the presence of
nasal polyps, caused by the dispersing of the ossa nasalia
by nasal polyps (Woakes Syndrome, typical for CF). A
horizontal nasal crease across the dorsum of the nose
supports a diagnosis of AR. The presence of vestibular
stenosis (Figure 3), alar collapse at the time of inspiration
(Figure 4) and/or narrow middle vault are associated
with nasal obstruction and can be observed during exter-
nal inspection of the nose during inspiration.

- The position: examination of the bony nose bridge,
mostly deviated by trauma, can be hampered by the
post-traumatic swelling. Examination of the cartilagi-
nous tip of the nose, mostly deviated during growth.

Figure 3 Inspection of the nose showing distortion of the
anatomy at the level of the nasal entry (in cleft lip patients)

Figure 4 Inspection of the nose showing alar collapse during
inspiration

- The covering skin of the nose: search for color
changes, edema, skin lesions, fistulas or scarification.

- The surrounding structures: forehead, eyes, cheeks
and upper lip.

II. Palpation
Rationale

This simple and inexpensive act is a proper manner to
trace pathology of the skin, the tissues, the bony and
cartilaginous parts of the nose.
Objectives

To evaluate the nose with the fingertips, in order to
search for shape or tissue anomalies, painful or sensitive
areas, and/or lack of tip support mechanisms.
Definition

Examination of the skin, underlying tissues, the bony
and cartilaginous parts for irregularities, abnormal mobi-
lity, pressure pain and tip support.
Technique/instrumentation

A proper light source is necessary for an accurate
inspection. With palpation one can detect a nasal valve
dysfunction, particularly with the Cottle test. The
cheek of the evaluated side is gently pulled laterally
with one or two fingers, which opens the valve. The
examiner then asks the patient to breathe and then
evaluates if breathing is subjectively better after pulling
the cheek. A positive test result is when the patient
feels less resistance with the valve opened. This test is
easy and quick to perform, but has a high false positive
result rate.

In case of lack of tip support, the tip elevation test
(Figure 5) may provide the examiner with valuable infor-
mation on the cause of nasal obstruction. The patient is
asked for improvement of nasal breathing by holding
the nasal tip in a position with a straight naso-labial
angle as depicted in Figure 5.

Anterior Rhinoscopy

Rationale

Anterior rhinoscopy makes a quick but limited internal
inspection possible of the anterior parts of the cavum
nasi.

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Figure 5 Tip elevation test for evaluation of improved
breathing by restoration of normal tip support

Objectives

An inspection of the clinical status of the anterior parts
of the nose. Trace nasal discharge or mucosal aberra-
tions like swelling, crusting, mucosal perforations, large
polyps.

Definition

Internal inspection of the vestibulum and cavum nasi
with the aid of an examination lamp fixed to a head-
band and a nose speculum (Figure 6).

Technique/instrumentation

With a forehead light and nose or ear speculum. Without
speculum, the tip of the nose can simply be pushed
upwards and so, one can get a first impression of the posi-
tion of the septum and of the head of the first concha
(practical in case of examination of an infant). A right-
handed observer takes the speculum in the right hand,
while the left hand is used to position the head of the
patient. The speculum, inserted under an angle of 45°,
spreads the alar cartilages and pushes aside the hairs in

Figure 6 Anterior rhinoscopy allowing the evaluation of
mucosal and/or anatomic pathology at the anterior part of the
nasal cavity

the nose. The nasal septum must not be touched, because
it is very sensitive. When the head of the patient is bend
forward, the anterior part of the inferior meatus and con-
cha can be visualized, by bending the head of the patient
backwards, the anterior part of the middle meatus and
concha. At last the speculum has to be removed closed to
avoid avulsion of the hairs in the nose, which is very pain-
ful. It must not be forgotten to get a look in the oral cavity
and pharynx for signs of pharyngitis, post nasal drip can
cause lymphoid hyperplasia, resembling cobble stones.

Nasal inspection can be supplemented by the so-called
mirror test (Figure 7). By holding a cold mirror or small
metal plate under the nostrils, the airflow during nasal
expiration can be assessed. A lack of fogging indicates
an inadequate nasal flow, or major asymmetrical fogging
indicates unilateral obstruction.

Sensitivity

Anterior rhinoscopy is limited in its evaluation of the
entire nasal cavity. Therefore, complete and thorough
examination using nasal endoscopy is advocated for
patients with nasal symptoms. For example, small polyps
may not be seen by anterior rhinoscopy.

Outcomes

Possible clinical findings during anterior rhinoscopy are
rhinorrhoe with transparent or discoloured secretions,
asymmetries (mostly of the nasal septum), mucosal
aberrations or edema, nasal polyps, neoplasms, corpora
aliena, etc. One can assess the accessibility of the nose
and the shape of the conchae.

Posterior Rhinoscopy

Rationale

This examination is performed to inspect the posterior
parts of the cavum nasi, the choanae, the posterior parts
of the lower and middle concha nasalis, the posterior

Figure 7 Mirror test for evaluation of the condensate of
expired air on a cold metal instrument or mirror

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septum, the nasopharynx with the adenoid and the ostia
of the auditory tube.

Definition

An inspection of the posterior parts of the cavum nasi and
the nasopharynx with the aid of a small throat mirror.

Technique/instrumentation

Posterior rhinoscopy is performed with a forehead light, a
tongue spatula in the left hand and a small throat mirror
in the right hand. Cooperation of the patient and skills of
the observer are required. Firstly, the mirror has to be
heated till body temperature, otherwise it will be dimmed.
Then the tongue spatula is placed in the middle of the
tongue base whereby the tongue will be pushed down
gently. The mirror can be advanced towards the space
beyond the uvula. The act has to be performed carefully
because touching the pharyngeal mucosa will trigger a
vomiting reflex. When the palatum molle is too stringent,
ask the patient to breathe calmly by the nose whereby the
palatum molle relaxes and so the view extends.

Outcomes

Possible conditions are congenital choanal atresia,
acute adenoiditis, irritation of the rhinopharynx, post-
nasal discharge, antro-choanal polyps, and Thornwald
cysts.

Recommendation

At present, this examination is not routinely being per-
formed, and is often replaced by nasal endoscopy.

Nasal Endoscopy (rigid and flexible)

Rationale

In comparison with the anterior and posterior rhino-
scopy, nasal endoscopy offers the advantage of global
evaluation of the endonasal cavity (Figure 8).

Objectives

Due to endoscopy, a good evaluation of the septum, the
whole nasal cavity and the nasopharynx is possible, but
also the area of the middle meatus which has clinical
importance in rhinosinusitis.

Definition

Nasal endoscopy allows inspection of the internal cavum
nasi, with a bigger range of view and details in compari-
son with anterior and posterior rhinoscopy.

Technique/instrumentation

Nasal endoscopy is performed by a flexible or rigid
scope which is attached to a strong light source by glass
fibre. For diagnostical examination, a scope with an
optic angle from 25-30° is used with a calibre of 2,5-4
mm (Figure 8). Other optics are mostly used in surgery.
Nasal endoscopy can eventually be preceded by local
administration of anaesthetic drugs preferably in combi-
nation with a decongestivum. At first, the bottom of the
nose unto the nasopharynx is to be inspected with an
evaluation of the septum nasi, the lower turbinate, the
choanae and the nasopharyx. Afterwards, the scope fol-
lows the edge of the middle concha towards the rostrum
sphenoidale, with information about the middle and
upper concha, the drainage from the sinuses, possible
accessory ostia from the maxillary sinus and the aper-
ture of the sphenoid sinus. At last, there must be
attempted to get a view of the osteomeatal complex, the
ethmoidal bulla and the access to the frontal sinus.

Outcomes

Allergic and inflamed mucosa, secretions or swelling in
the middle meatus, and possible presence of nasal
polyps should be evaluated. Although the usefulness of
nasal endoscopy in the evaluation of the nasal conges-
tion is obvious, no clinical trials were found to support

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this statement. It was shown to be moderately sensitive
and highly specific in predicting CT scanning results in
patients with CRS [32] . Nasal polyps can be viewed with
endoscopy, their presence and severity can be scored by
validated systems with a good reproducibility. However,
a correlation between size of polyps and the subjective
symptom of congestion cannot be found. This discre-
pancy between objective findings and subjective com-
plaints make endoscopy less suitable for assessment of
severity. Still, when nasal polyps are present, nasal endo-
scopy scoring is very useful in treatment evaluation [33].
A possible semi-quantitative score for nasal polyps can
be obtained at baseline and at regular intervals following
therapeutic interventions (Table 2).

Diaphanoscopy of the frontal and maxillary sinus

Definition

Transillumination of human tissue or a cavity, like a
sinus, with a light source to evaluate the opacity of the
hollow sinus.

Technique/instrumentation

Transillumination of the maxillary sinus is performed
with a light source in the mouth of the patient,
watched in a darkened room. If the sinus is accessible
(vacant), the light shines through the sinus and
through the pupil. The frontal sinus can be investi-
gated by diaphanoscopy if the light source is placed at
the bottom of the frontal sinus. This examination is
only useful in case of a unilateral acute maxillary or

Table 2 Endoscopic appearance scores

Characteristic Baseline and Follow-up

Polyp left (0,1,2,3)
Polyp right (0,1,2,3)
Oedema left (0,1,2)
Oedema right (0,1,2)
Discharge left (0,1,2)
Discharge right (0,1,2)

Postoperative scores to be used for outcome assessment only

Scarring left (0,1,2)

Scarring right (0,1,2)

Crusting left (0,1,2)

Crusting right (0,1,2)

TOTAL POINTS

Polyps: 0 Absence of polyps

1 Polyps in the middle meatus only

2 Polyps beyond the middle meatus but not blocking the nose completely

3 Polyps completely obstructing the nose
Oedema: 0 Absent; 1 Mild; 2 Severe

Discharge: 0 No discharge; 1 Clear, thin discharge; 2 Thick purulent discharge
Scarring: 0 Absent; 1 Mild; 2 severe
Crusting: 0 Absent; 1 Mild; 2 severe

frontal sinusitis of an adult patient, who did not yet
undergo sinus surgery.

Although the shortcomings of diaphanoscopy soon
became apparent, the method was widely used for about
half a century, but in the end could not compete with
modern techniques of radiography and ultrasound [34].

Recommendations

Inspection, palpation and anterior rhinoscopy are easy
and rapid ways to examine a nasal problem without
inconvenience to the patient. Therefore they should be
the corner stone of every physical examination. Anterior
rhinoscopy allows a limited internal inspection of the
nasal cavity. In the majority of patients with persistent
nasal symptoms, a complete and thorough examination
of the nasal cavity is warranted using nasal endoscopy.
For example, small polyps may not be seen by anterior
rhinoscopy. Nasal endoscopy has been particularly use-
ful in assessing the nasal airways in the region just
below the olfactory cleft. Rigid endoscopy has proven to
be more patient friendly and supplies a better image
than flexible endoscopy. Patients awarded each type of
scope a pain score on an analogue scale, according to
the level of discomfort experienced, and the operator
noted the number of structures seen. Significantly more
structures were visualized with the rigid scope than the
flexible scope. The pain scores were similarly in favor of
the rigid scope, showing a trend to less discomfort [35].

Allergy Tests Including Provocation

Rationale and objectives of diagnostic tests in allergy

In the diagnostic process of allergic rhinitis we assume
that allergen-specific IgE is the triggering factor of
symptoms and of the underlying inflammatory process.
Thus, the main goal of the diagnostic tests is to demon-
strate both the presence and functional relevance of
such IgE. In fact, the presence of specific IgE alone (sen-
sitization) does not necessarily imply the existence of
allergic symptoms, and there are a relevant number of
individuals who are sensitized but who are not clinically
allergic [36].

In patients with symptoms suggestive of AR, further
diagnostic testing is required for optimal diagnosis and
management (Figure 9). The presence of specific IgE can
be demonstrated either in vivo (skin tests, SPT) or in
vitro by detecting allergen-specific IgE in the blood
(RAST, CAP-RAST and equivalent assays). Currently,
SPT are unanimously considered the gold standard and
the first-line approach for the detection of allergic sensi-
tization, due to its' efficiency, safety and relatively low
costs. The biological assays (CAP-RAST) have an equiva-
lent efficiency, but due to costs are considered a second
choice to be used only in special situations. The basophil
degranulation tests require a special laboratory apparatus

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r

SYMPTOMS OF AR

SKIN PRICK TEST

Negative/not feasible
discordant from
clinical hsitory

Positive and in
agreement with
clinical hsitory

SPECIFIC IgE

DIAGNOSIS
OF AR

Negative/not feasible
discordant from
clinical hsitory

NASAL CHALLENGE
(search for nasal IgE?)

AR EXCLUDED «-

Negative

Figure 9 Diagnostic algorithm for the diagnosis of AR.

and, therefore, do not represent a routine option in the
diagnostic workup. In addition, the functional role of spe-
cific IgE can be demonstrated in vitro by basophil activa-
tion tests or in vivo by the allergen-specific provocation.

The nasal provocation tests aim at eliciting a nasal
response, by delivering appropriate allergens to the
nose. There is a wide variability of substances, measure-
ments and evaluation techniques for nasal challenges
(Figure 10). The purpose of the allergen specific provo-
cation, is to reproduce at some extent the reaction
occurring during the natural exposure to allergens.
Thus, nasal allergen challenges allow demonstrating
both the presence of allergen-specific IgE and the causal
role of the allergen. The same happens with occupa-
tional substances or with aspirin, although in these cases
the mechanism maybe non IgE-mediated. The non aller-
gen- specific challenges evoke a non-specific

STIMULUS

Allergen

Histamine

Methacholine

Hyperosmolar solution

Adenosine

Mannitol

DELIVERY

Powder
Solution
Paper disks
Challenge chamber

ASSESSMENT:

Symptom score
Inspection of mucosa
Weight of secretions
Number of sneezes

Nasal flow/patency ►

Rhinomanometry
Acoustic rhinometry
Peak flow

Cytology
Mediators

Brushing, scraping

Cytokines
NO

Biopsy
Lavage

Figure 10 Practical approaches for nasal provocation test.

inflammatory response, and demonstrate the existence
of a nasal hyperreactivity.

Skin prick test (SPT)

The SPT technique is currently considered the gold stan-
dard method for the diagnosis of allergic rhinitis. With a
trained investigator, they are highly reproducible [37,38].
Prick tests should be performed according to a rigorous
methodology, with standardized diagnostic extracts, and
always must include a negative (saline or diluent) and a
positive control (histamine HQ 0.1%). Skin tests should
be read at the peak of reaction (approximately at 15 min-
utes) by measuring the extension of wheals (Figure 11).
The diagnostic and clinical significance of late reactions
is not known. The scoring of the positivity is given
according to EAACI recommendations, and the interpre-
tation of a positive test must be integrated with the clini-
cal history, since a positive SPT does not always imply a
clinically relevant sensitization.

False positive reactions may occur, if a dermographism
is present, but this can be ruled out with the use of the
negative control.

False negative may occur due to:

a) weak potency of the extract;

b) inadequate technique (weak puncture);

Figure 11 Skin prick test with evaluation of wheal and flare
reaction on the skin at the site of allergen deposition

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c) interfering drugs. Systemic antihistamines are the
most important drugs that reduce the skin reaction
(Table 3). Thus, antihistamines must be discontinued at
least 5 days before the SPT (for review see 11). On the
other hand, antileukotrienes do not interfere with SPT
and can be continued [39].

Intradermal tests are not of choice for the diagnosis of
respiratory allergy, since they do not perform better than
SPT and can induce false positive results. On the other
hand, intradermal tests remain an essential part of the
diagnostic workup for hymenoptera allergy [40]. The
scratch test is no longer in use.

Atopy patch tests involve epicutaneous patch tests
with allergens known to elicit IgE-mediated reactions.
Commercial reagents are available for a few allergens,
and have been standardized regarding the use of vehicle
and dose-response relationships. A subset of patients
with atopic dermatitis show only atopy patch test posi-
tivity while specific IgE to the same allergen remains
negative [41], but the atopy patch test is usually not
relevant for the diagnosis of respiratory allergies.

Detection of allergen-specific IgE

The first method used for the measurement of serum
allergen specific IgE has been the radioallergo sorbent test
[42]. This has been now replaced by immune-enzymatic
methods, including the widely used CAP assay. With these
assays the level of specific IgE is expressed as kU/L,
according to calibration curves, and the cut-off IgE level
above which the test is positive is usually 0.35 KU/1. How-
ever, some sensitized subjects have an IgE level below this
cut-off. The measurement of serum-specific IgE is usually
less sensitive than skin prick tests [43] and the worst cor-
relations between SPT and IgE assays are obtained with
mold, food extracts and non standardized extracts. In gen-
eral, the correlation between a strongly positive response
to a skin test and the detection of serum-specific IgE and
between a negative response to a prick test and the lack of
detection of serum-specific IgE is very good. As in skin
tests, the presence or absence of specific IgE in the serum
does not imply a clinically relevant allergy. As mentioned
above, for inhalant allergens, skin test responses represent

the first-line diagnostic methods and when they correlate
with the clinical history, in vitro tests are not necessary [1].

It has been suggested in the past that some patients
may have a local IgE immune response without systemic
IgE [44]. It has been recently shown that in a subset of
patients the presence of specific IgE in the nasal mucosa
can be demonstrated [45]. Nonetheless, the measure-
ment of IgE in nasal secretions cannot be routinely
proposed.

The presence of functionally relevant specific IgE can
be demonstrated by putting the allergen into contact
with basophils and subsequently detecting their activa-
tion by cytofluorometry. This basophil degranulation
test has been proposed for specific conditions, such as
drug allergies, but is not recommended at all for the
diagnosis of respiratory allergies, and it is used only for
research purposes.

Serum-total IgE is measured using either radioimmu-
noassay or enzyme assay. In normal subjects, levels of
IgE increase from birth to adolescence and then
decrease to reach a plateau after the age of 20-30 years.
In adults, levels of over 100-150 KU/1 are considered to
be above normal. Nevertheless, an increase of total IgE
correlates weakly with the presence of allergic diseases.
Total IgE maybe increased in other conditions such as
smoke and parasitic diseases. Thus, the measurement of
total-serum IgE should no longer be used for screening
or allergy diagnosis [1].

Allergen specific nasal challenge (ASNC)

The ASNC procedure, also known as specific nasal pro-
vocation test (SNPT) or nasal allergen challenge (ANC)
involves the delivery of a small quantity of the allergen
into one (or both) nostril, in order to elicit the allergic
reactions, if allergen-specific IgE is present in the nasal
mucosa. By using progressively increasing amounts (or
concentrations) of the allergen, a threshold dose can be
also established. Recently, the availability of recombinant
purified allergens has suggested the possibility to per-
form challenges with each specific allergenic protein,
but the role of such approach in clinical practice is still
not defined.

Table 3 Drugs affecting the results of skin tests

Suppression

Duration of Suppression (days)

Cetirizine, desloratadine, ebastine, levocetirizine, mizolastine

++++

3-10

Chlorphenamine, promethazine

++

1-3

Ketotifen

++++

>5

mipramine

++++

>10

Inhaled steroids

Systemic steroids

+/-

Cimetidine/ranitidine

Antileukotrienes

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The procedure of allergen provocation was proposed
more than one century ago and began to be systemati-
cally investigated starting from the 1950ties. Nowadays,
there are some official documents available, where an
attempt to standardize the procedure has been made
[46]. The main advantages of ASNC are the simplicity
of execution, the low cost and the safety. On the other
hand, the procedure is still poorly standardized and the
technical details (amount of allergen, interval between
doses, dilutions, positivity criteria) are largely variable
among centres. The main indications of ASNC are

a) to demonstrate the causal role of an allergen,

b) to identify the clinically relevant allergen(s) in poly-
sensitized subjects,

c) to evaluate the effects of a treatment

d) to study the inflammatory phenomena (Table 4)

e) to evaluate the role of occupational allergens.
When an allergen is introduced into the nose, the IgE-

mediate reaction immediately takes place and the classic
symptoms appear within seconds. Symptoms slowly sub-
side within 4-6 hours, may re-appear after several hours
in case of a late phase reaction. The biphasic reaction
can be easily demonstrated by nasal scrapings to assess
the presence of the inflammation.

The SNPT can be evaluated in many different ways.
The most common and practical is the measurement of
the four classic nasal symptoms by an ordinal scale (0 =
absent to 3 = severe), being the test positive if a cumula-
tive score of 5 or more is obtained. Alternatively, a
visual analog scale can be used. Another semi-quantita-
tive evaluation is the weight of nasal secretions, but this
is less practical and is used only in research settings.

A quantitative assessment of the ASNC can be made
by instrumentally measuring the nasal flow or resistance,
by nasal peak flow meter, acoustic rhinometry or rhino-
manometry. These investigations will be dealt with
further in the document.

Other possible modalities to evaluate the effect of
allergen challenge are the assessment of the inflamma-
tory infiltrate by nasal scraping/brushing (with differen-
tial cell count), or the measurement of specific
mediators in nasal lavage, including tryptase, alpha2
microglobulin, albumin, leukotriens, interleukins, eosi-
nophil cationic protein and others (36-40).

Aspirin nasal challenge

The nasal challenge with aspirin is not truly an allergen
challenge, since an IgE mediated mechanism is not
involved. Nevertheless it has the value of a specific chal-
lenge and it is used to diagnose aspirin intolerance in
the context of the aspirin hypersensitivity with respira-
tory manifestations. The nasal challenge with aspirin
was introduced later than the oral and bronchial chal-
lenge [47], but has gained popularity since it rarely
induces systemic reactions. Nasal aspirin challenge is
used in patients with severe asthma in whom oral or
bronchial aspirin challenges are contraindicated.

The aspirin challenge is sufficiently standardized and
reproducible [48], although the possibility of false nega-
tive results exists and the negative predictive value is
lower than the oral and bronchial challenges. For this
reason, it is agreed that where an aspirin intolerance is
suspected and the nasal challenge is negative, the oral
challenge must be performed. The nasal aspirin challenge

Table 4 Practical aspects of ASNC

CONTRAINDICATIONS

Acute bacterial or viral rhinosinusitis.
Acute exacerbation of allergic disease.
History of previous anaphylactic reaction
Severe general diseases
Pregnancy
Polyps

Recent ENT surgery (6-8 wks)

CAUSES OF FALSE NEGATIVE

Weak extract
Drugs

nasal antihistamine (1 day withdrawal)
oral antihistamine (3 day withdrawal)
nasal steroid (7 day withdrawal)

GENERAL PROCEDURE

Let the patient be adapted to room temperature
Inspect nasal cavity

Spray or apply saline as negative control
Perform measurement(s)
Instruct to avoid nasal breathing

Apply the allergen into one nostril and re-evaluate after 10-15 minutes

Proceed on with increasing concentration in the other nostril

Use both active and plasebo tests for diagnosis for occupational rhinitis

PURPOSES

Demonstration of the causal role of an allergen
Identification of the most relevant allergen(s)
Evaluation of the effect of a treatment
nvestigating the inflammatory phenomena (research)
Occupational rhinitis

CAUSES OF FALSE POSITIVE
Nasal cycle

Recent exposure to irritants

Rhinosinusitis

Priming effect

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must be performed under medical supervision. Oral,
nasal steroids and antileukotrienes should be discontin-
ued at least 7 days before, whereas the withdrawal period
is 3 days for antihistamines and 24 hours for deconge-
stants and cromones. Lysine-aspirin solutions at 0.1, 1
and 2 M are used at 10-minute interval steps. The eva-
luation of the result can be either clinical (symptoms) or
instrumental (acoustic rhinometry, anterior rhinomano-
metry), and pulmonary function must be monitored dur-
ing the challenge.

Non-specific nasal challenges

Nasal hyperreactivity is the capacity of the nasal mucosa
to respond with clinical symptoms and inflammation to
unspecific stimuli, which are not causing any mucosal
reaction in normal subjects. Nonspecific nasal reactivity
is common in patients with allergic rhinitis [49]. A wide
variety of stimuli can be used to evoke nasal hyperreac-
tivity. These stimuli may directly act on a single recep-
tor such as histamine, adenosine monophosphate, and
methacholine, or activate a more complex mechanism,
such as mannitol, capsaicin, hyperosmolar solutions and
cold air.

The results obtained with non-specific nasal chal-
lenges are often conflicting and difficult to interpret,
due to the heterogeneity of methods, doses and out-
comes. As an example, histamine and methacholine are
both able to evoke a nasal reaction, that is more pro-
nounced in subjects with rhinitis than in healthy con-
trols [50], but only histamine is able to modify the nasal
resistance. On the other hand, cold dry air was shown
capable of differentiating between patients with peren-
nial non-allergic rhinitis and healthy subjects, but hista-
mine did not [51]. In addition, mannitol nasal challenge
seems unable to activate mast cells, although a dose-
response in eliciting symptoms has been reported for
this test [52].

The adenosine monophosphate challenge is relative
simple and reproducible and more sensitive than hista-
mine challenge [53]. It has been proposed to predict the
response to nasal steroids and as a surrogate marker to
evaluate the anti-inflammatory effects of drugs.

Nasal capsaicin challenge displays a dose-dependent
response [54], and is able to detect the nasal hyperreac-
tivity in seasonal allergic rhinitis. Due to its selectivity
for sensory nerves, it is mainly used for experimental
purpose to study the cough reflexes.

The nasal provocation with cold dry air requires a
special apparatus, and is currently used only for
research purposes. Interestingly, the cold air provoca-
tion has been reported to be able to discriminate
between rhinitis alone and rhinitis associated with
asthma [55], and between non-allergic rhinitis and
healthy subjects [51].

A threshold dose discriminating healthy and diseased
subjects has not been univocally established, as happens
for instance in asthma. Another problem with those
tests is that only few of them has been sufficiently stan-
dardized. Finally, the role of nonspecific hyper-reactivity
in distinguishing different forms of rhinitis has not been
established yet. Thus, for the clinical purpose and diag-
nosis of allergic rhinitis, the use of non-specific tests is
not essential.

Assessing the sense of Smell

Rationale

Several patients with rhinitis and/or rhinosinusitis com-
plain of smell dysfunction, and treatment for these con-
ditions aims at restoring olfaction.

Objectives

To objectively evaluate the capacity of an individual to
smell environmental odours.

Techniques

Several techniques are currently available for the objec-
tive evaluation of an individuals' smell capacity. The dif-
ferent tests that have been reported in the literature are
listed below and extensively described in the Appendix,
with emphasis on their clinical use, validation and
strengths and weaknesses.

List of different diagnostic smell tests (Appendix 1)

University of Pennsylvania Smell Identification Test
(UPSIT)

Connecticut Chemosensory Clinical Research Center
Test (CCCRC)
Smell diskettes test
Odourant confusion matrix
Dutch odour identification test (GITU)
YN-odour Identification Test (YN-OIT)
T&T Olfactometer

San Diego Odor Identification Test (SDOIT)

Cross-Cultural Smell Identification Test (CC-SIT)

Combined olfactory test (COT)

Sniffin'-Sticks

Candy smell test (CST)

Alcohol Sniff Test (AST)

Culturally Adjusted University of Pennsylvania Smell
Identification Test (CA-UPSIT)
Kremer smell test

Scandinavian Odour-Identification Test (SOIT)

Pocket Smell Test [56]

Eloit and Trotier Olfactory Test

Ramdon Test

Four-minute odour identification test
Barcelona Smell Test (BAST-24)
Nez du Vin smell test

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Recommendations

Smell testing should be an integral part of the diagnostic
approach in patients with smell dysfunction, i.e. hypos-
mia, parosmia or anosmia as presenting symptoms of
sino-nasal disease, post-traumatic or post-viral smell dis-
order. Smell dysfunction is a cardinal symptom of rhino-
sinusitis with/without nasal polyps, but novel data
suggest that also allergic rhinitis is often associated with
a subjective reduction in smell capacity.

Assessing the Sense of Taste

Objectives

To evaluate the capacity of taste of five basic taste sen-
sations, i.e. salt, bitter, sour, umami and sweet, in
patients complaining of dysfunction of smell and taste.
Smell disorders may be associated with disturbed taste
capacity, hence necessitating the evaluation of taste
capacity in addition to smell capacity in these patients.

Techniques

Gustometry with application of taste substances and elec-
trogustometry are the methods of taste examination.
There are various ways of applying taste substances during
gustometry examination. The stimuli used in gustometry
are: citric acid or hydrochloric acid (sour taste), caffeine or
quinine hydrochloride (bitter taste), sodium chloride (salty
taste), saccharose (sweet taste), monosodium glutamate
(umami taste). Electrogustometry, widely used by clini-
cians to examine taste sensitivity, allows estimating the
functioning of taste by means of electric excitability
thresholds determined through the response to the irrita-
tion of taste buds area with electrical current of different
intensity. Electrogustometry is especially useful in estimat-
ing the efficiency of sensory pathways. However, if we
want to examine taste sensitivity to individual taste cate-
gories we should use more laborious gustometry with the
application of taste substances, which main advantage is
the use of physiological stimuli [57]. Taste impairment
may provide a good indicator to the course of some
diseases such as diabetes mellitus in which hypogeusia
predicts occurrence of degenerative complications.
Dysgeusia may induce nutritional disorders and contribute
to wasting in chronic liver disease, cancer, or human
immunodeficiency virus infected patients. Mechanisms
involved in dysgeusia are more than one in a patient.
Taste disturbance may be secondary to a variety of causes
that include zinc deficiency, lesions of the lingual epithe-
lium, neurological impairment, and adverse events of
medication.

Recommendations

Testing the taste capacity represents a diagnostic tool
that is helpful in the clinical discrimination of smell and
taste disorder in patients with smell problems

complaining of combined loss of smell and taste, and in
patients with isolated taste disorders.

Nasal Nitric Oxide

Definition

Nitric oxide (NO) is a colourless, odourless gas that is
present in air exhaled through the mouth or nose. NO is
produced from arginine and oxygen by nitric oxide
synthase (NOS). Constitutively expressed neuronal and
endothelial forms exist as well as an induced form, iNOS,
which appears to be up regulated within the respiratory
tract in response to pro-inflammatory signals. NO came
to prominence for its role in vasodilatation [58] and sub-
sequently as a neurotransmitter and inflammatory media-
tor [59]. The role of NO in the airways is complex,
possibly including antibacterial effects, pro-inflammatory
effects, and regulation of blood flow and ciliary beat fre-
quency. Exhaled NO (eNO) levels are raised in eosino-
philic asthma [60] and measurement of this has become
a standardised, but not yet widespread, tool in diagnosis
and management of asthma. It can potentially provide a
rapid, low cost, objective measure of lower airway
inflammation.

Far greater levels of NO are produced in the upper
than in the lower respiratory tract, with contributions
from the sinuses and to a lesser extent from the nasal
mucosa [61].

Objectives

Measurement of nasal NO (nNO) may represent a use-
ful tool for research purposes as well as for sreening for
PCD. Nasal nitric oxide may be normal, raised or low-
ered in disease states; however measurement may be a
useful tool in the diagnosis and management of patients
with chronic rhinosinusitis, nasal polyps, and CF, as well
as in the diagnosis of PCD. Measuring both bronchial
and nasal nitric oxide may assist the combined manage-
ment of upper and lower airways.

Nasal NO

High levels of NO are produced constitutively in normal
individuals within the paranasal sinuses by calcium-inde-
pendent nitric oxide synthase, with levels measured at
20-25 ppb [62]. Additionally, nitric oxide is also formed
in the nasal mucosa by inducible NOS (iNOS) in
response to inflammation. NO and its metabolites are
toxic to micro-organisms and likely form part of the
innate defense mechanism of the respiratory tract. NO
may also stimulate cilia beat frequency within the epithe-
lium and regulate nasal vascular tone.

Technique

As for eNO, nNO can also be measured by chemillumi-
nescence, using non-invasive techniques, providing

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immediate results. A number of different techniques have
been used to ensure sampling from the upper airways only
including breath holding and breathing against resistance.
Guidelines for measurement have been published [63].

Sensitivity and specificity

In contrast to measuring eNO, high baseline levels in
nNO make background environmental NO levels less of
a problem. Conversely, there is a high degree of inter-
individual variability amongst healthy controls. More-
over, there is also a significant degree of intra-individual
variation over time, meaning that changes of 20-25% or
less may be accounted for by normal variation rather
than change in disease status or response to medication
[64]. Additionally, the lack of universal standardization
of testing procedures means levels recorded by different
study groups vary considerably even amongst equivalent
patient populations. The factors affecting eNO levels
such as recent exercise or time of day, may similarly
affect nNO measurements. Local factors such as nasal
volume and patency may also be important.

Outcomes

Despite the above limitations nNO has a number of
potentially useful clinical applications. With regards to
diagnosis, nNO is useful as a screening tool for patients
with possible PCD; levels less than 100 ppb, particularly
if these persist following decongestion, should stimulate
investigation of mucociliary structure and function. The
test is objective and may be easier to perform than a sac-
charine clearance test in younger children. Similarly,
nNO may provide a useful tool in diagnosis of CF in the
context of upper respiratory tract symptoms; levels sig-
nificantly lower than in controls have been reported in
some studies, but not others. nNO has a potential role in
the diagnosis and assessment of CRS, especially when
associated with NP. Interestingly, despite the increased
expression of iNOS in polyp epithelium [65], low nNO
levels have been found in two large studies [66]. More-
over, nNO inversely correlated with endoscopic NP size,
CT scores and clinical severity of disease [67]. Conver-
sely, in a study involving chronic rhinosinusitis patients
with and without polyps, no correlation between nNO
and CT scores was found, although patients were again
found to have lower baseline nNO than controls [68].

Low nNO levels in chronic rhinosinusitis are thought
to reflect obstruction at the sinus ostium and impairment
of gas transfer out from the sinuses. This is supported by
the finding of raised nNO following medical and surgical
[65] treatment of rhinosinusitis with or without polyps.

A number of recent studies have focused on the possi-
ble use of humming to improve the sensitivity of nNO
measurements. Weitzberg and Lundberg [69] found that
humming induced a large increase in nNO and that these

increases were not detected in patients with nasal polyps
and sinus ostium obstruction. Furthermore, they suggest
that absence of a normal response to humming during
nNO measurement could be used to identify allergic rhi-
nitis with sinus ostium obstruction. Whether this adds
significant value to standard testing has yet to be fully
appreciated.

Recommendations

Nasal NO is a useful measure to alert the clinician to a
possible defect in mucociliary clearance (PCD, CF) and
may have in the evaluation of the patency of the sinus
ostium Variable baseline levels of nNO and the modest
changes which may occur in allergic rhinitis or following
treatment make nNO measurement of little value in the
diagnosis and management of uncomplicated rhinitis.

Nasal Sampling: lavages, cytology, biopsies

Rationale

Inflammation of the nose and sinuses is represented
within the nasal mucosa and secretions. A variety of
approaches have been used to monitor nasal inflamma-
tion to investigate disease processes and to evaluate the
effect of therapeutic intervention. These approaches
include nasal lavage, different ways to obtain nasal cytol-
ogy, nasal biopsy, and nasal NO-measurements.

Objectives

To compare different sampling methods of the nose and
indicate the strength and weaknesses.

Techniques

Nasal blown secretions

In this method, secretions in the nasal airways are
blown onto wax paper or a plastic wrap and then placed
onto a glass slide. Microscopic evaluation allows the dis-
crimination of epithelial cells from granulocytes.
Nasal lavage

Nasal lavage is the introduction of fluid into the nasal cav-
ity and its recovery after a predetermined dwell time.
Nasal lavage is simple and rapid to perform, is well toler-
ated, and provides a sample that allows us to evaluate the
content of the secretion in the nasal lumen such as pro-
tein, cells, mediators and cytokines. A range of techniques
has been used to instil and recover fluid from the nasal
cavity. Usually a volume of 2.5 mL to 5.0 mL 0.9% NaCl,
prewarmed to 37°C, is instilled within each nostril with an
80% recovery (range, 65% to 90%). An agent to disrupt the
disulphide bonds of the mucus polypeptide chains can be
included. In situations of extreme nasal blockage, the
obstruction of the nasal lumen will limit the amount of
fluid that can be retained within the nasal cavity, and
smaller lavage volumes need to be used under such cir-
cumstances. The consistency of the findings in allergic

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and infective rhinitis for a range of different measures in
nasal lavage fluid supports the concept that this method of
nasal evaluation provides reliable information of relevance
to disease activity although normalization of the variable
recovery can be difficult. However, repeated nasal lavage is
associated with a significant reduction in histamine con-
centration. Also there is considerable variability between
subjects in eosinophil luminal recruitment and activation.
Sinus packs or filter paper

Pre-weighed sinus packs are placed on the floor of the
nasal cavity between the septum and inferior turbinate for
5 min and then placed back in a Falcon tube [70]. In order
to mobilize the nasal secretions out of the sinus pack, the
sinus pack is washed with 3 ml of 0.9% NaCl solution. The
sinus pack is then placed into the shaft of a syringe and
the sinus pack is squeezed by moving the piston of the syr-
inge. After this first pressure the shaft containing the sinus
pack is placed into a Falcon tube and centrifuged at 1,500
g for 10 min to recover all fluid.

If irritation of the nasal mucosa is an issue, thin filter
paper that can be inserted without touching the nasal
mucosa, can be used instead of sinus packs. The amount
of secretion that can be absorbed in this way is however
more limited [71,72].
Microsuction technique

Nasal secretions can be collected by direct aspiration as
has been described by Biewenga [73] . The samples can be
collected by repeated aspiration into a pre-weighed plastic
sampling tube immediately followed by aspiration of a
known volume (1.0 ml) of PBS containing 10% of Mesna.
Mesna acts by disrupting the disulphide bonds of the
mucus polypeptide chains, and is necessary to obtain a
good quality supernatant. The direct aspiration system
combines the advantages of minimal irritation of the nasal
mucosa with the facility to determine concentrations per
gram of secretion.
Nasal brush

A small nylon brush used for cell sampling, is intro-
duced in the middle meatus of the nose and turned
carefully. The brush is immediately placed in a 5 ml
polystyrene plastic tube containing 5 ml of PBS and is
cut off just above the bristles. The brush can then be
shaken vigorously in the solution and carefully brushed
off against the wall of the tube. The tubes are centri-
fuged at 400 g for 10 minutes [74]. Both the supernatant
and cells can be used for analysis. Nasal brush give
information on living epithelial cells which is an advan-
tage over nasal lavage, however the sampled area is
smaller. Brushing can reliably be used in babies and
small children [75].
Nasal scraping

Nasal scraping can be performed with the Rhinoprobe
[76,77]. The cupped tip of the disposable probe is gently
passed over the mucosal surface of the medial aspect of

the inferior turbinate. Two or three short scrapes of the
epithelial layer are made to obtain a sample. The speci-
men is spread onto a plain slide and immediately fixed
for at least 1 minute in 95% ethyl alcohol. Nasal scrap-
ings give information on living epithelial cells sometimes
in larger lumps which is an advantage over nasal lavage,
however the area sampled is smaller than lavage and
brush.

Nasal biopsy specimens

Biopsy specimens can be taken from the nasal mucosa,
usually from the inferior turbinate. High quality 2.5-mm
biopsy specimens can be taken under direct vision with
nasal biopsy forceps, such as Gerritsma forceps (Fok-
kens' forceps), without visible damage to the epithelium
of the sample and with sufficient depth of lamina pro-
pria [78]. Local anaesthesia can be achieved by placing a
cotton-wool carrier with 50 to 100 mg of cocaine and 3
drops of epinephrine (1:1000) under the inferior turbi-
nate without touching the area from which the biopsy
specimen is taken. For light microscopic evaluation, the
biopsy specimens are embedded in Tissue-Tek II OCT
compound in a gelatin capsule and frozen immediately.
Biopsies can be taken a number of times within one
patient without causing significant problems [79]. The
minimum number of sections required to give a suffi-
cient number of fields to assure acceptable accuracy
(5%) was determined to be 2 on the basis of a summa-
tion average graph [80].

Comparison of different techniques

A comparison of the different techniques is shown in
Table 5. The choice of the technique depends on the
diagnostic or research question asked.

Data on the comparisons between different techniques
are limited, but cells and mediators within nasal lavage
have been reported to show some correlation [81].

Cells determined by nasal brush has been shown to be
comparative to nasal lavage after nasal allergen provoca-
tion [82]. Two studies show moderate to good correlation
between cells recovered from biopsy and brush [83],
however in one of these studies in which repetitive nasal
provocations were given the number of inflammatory
cells differed considerably on a day to day base [84].

Evaluation of Nasal Patency

Rationale

One of the primary functions of the nose is to humidify,
filter and warm the inspired air. A patent nose with lack
of anatomic and/or mucosal disease is a prerequisite for
the transport of inspired air from the nose to the lower
airways. A proper clinical examination of the nose
allows the clinician to evaluate the nasal function.
Inspection of the nose at rest and during inspiration
may show normal anatomy or pathology causing

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Table 5 Comparison of different techniques

Method

Advantage

Disadvantage

Nasal blown secretions

- easy to perform

- subject must be able to blow nose

- no information about mucosa

Nasal lavage

- easy to perform

- luminal proteins, cells, mediators and cytokines

- reliability depends ability of subject to close nasopharynx

- dilution of mediators and cytokines

- variable recovery of fluid

- no information about mucosa

Sinus packs or filter paper

- no/limited dilution of mediators

- may irritate the nose

- cannot collect cells

- no information about mucosa

- more difficult than lavage

Microsuction technique

- no dilution of mediators

- representative sample?

- technically difficult

- cannot collect cells

- no information about mucosa

Nasal brush

- sample of epithelium

- no sample of deeper layers

- no information about nasal lumen

- technically more difficult

Nasal scraping

- sample of epithelium

- no sample of deeper layers

- no information about nasal lumen

- technically more difficult

Nasal NO

- non-invasive

- measure of inflammation and blockage

Nasal biopsy

- sample of total nasal mucosa

- no information about nasal lumen

- technically difficult

impaired nasal functioning like vestibular stenosis, col-
lapse of the nostrils during inspiration called alar insuffi-
ciency, asymmetry in the nostrils or severe nasal septal
deviation. Anterior rhinoscopy enables the clinician to
distinguish between mucosal and anatomic problems
associated with nasal dysfunction. Other clinical tools
like nasal endoscopy and posterior rhinoscopy allow
experienced clinicians to evaluate the entire endonasal
cavity and nasopharynx including the choanal region
respectively.

A more objective evaluation of nasal patency may be
required in patients suffering from nasal obstruction
due to anatomic or mucosal pathology, or in the context
of provocation studies and clinical trials. Nasal patency
can be assessed by different means, each technique deal-
ing with a different aspect of patency: nasal flow, nasal
cross-sectional diameter and nasal resistance during
respiration. An overview is provided on the different
techniques with technical aspects, advantages and disad-
vantages of every technique and recommendations for
use in practice.

Objectives

Nasal obstruction is often reported by patients with ana-
tomic or mucosal nasal disease and can be scored sub-
jectively on a visual analogue (VAS) scale. Objective
evaluation tools of nasal obstruction are often warranted
in patients suffering from nasal obstruction or for eva-
luation of mucosal changes in provocation studies or
clinical trials.

Nasal patency can be monitored objectively by mea-
suring the following parameters:

1/nasal air flow passing through the nose during nasal
respiration, evaluated with the nasal peak inspiratory
and expiratory flow (PNIF and PNEF)

2/the volume of the nasal cavity evaluated with acous-
tic rhinometry and

3/the nasal airflow and pressure during nasal respira-
tion evaluated with rhinomanometry.

Differences exist in indication for clinical use of each
technique, the interpretation of the results, the valida-
tion of the technique, and the cost of the equipment.

Definitions

1/Peak nasal inspiratory flow (PNIF)

Nasal peak flow evaluation (Figure 12) represents a physio-
logic measure of the air flow through both nasal cavities
during forced inspiration and/or expiration expressed in
liter per minute. The PNIF is the best validated technique
for the evaluation of nasal flow through the nose. Nasal
inspiration correlates most with the subjective feeling of
obstruction and is the best validated technique for moni-
toring nasal flow in clinical trials and after nasal provoca-
tion. In contrast to PNIF, PNEF is less validated and used
in clinical practice in view of the mucus being blown into
the peak flow meter and subjective discomfort during
maximal expiration in patients with mucosal disease [85].
2/Rhinomanometry

Active anterior rhinomanometry (Figure 13) represents a
physiologic measure of nasal air flow and pressure during

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Figure 12 Peak nasal inspiratory flow measurement.

normal inspiration and expiration. It is considered the
standard technique for the evaluation of nasal airflow
resistance, hence providing a functional measure of nasal
patency. Depending on the position of the probes for
registration, anterior or posterior rhinomanometry can
be performed, both being valid techniques. When the
probe is placed in the mouth, posterior rhinomanometry
values can be obtained for both nasal cavities together or
for one nasal cavity when sealing of one nostril. In ante-
rior rhinomanometry, the pressure-sensing tube is placed
in one nostril and data represent unilateral pressure and
flow measures. The anterior rhinomanometry is often
recommended for its' ease of use.
3/Acoustic rhinometry

Acoustic rhinometry is a non-physiologic measure of
nasal patency, measuring echoes of sound impulses sent
into one nostril (Figure 14). The measurement provides
information on the nasal luminal anatomic structures,
either as a measure of nasal volume over a standard dis-
tance into the nostril or as the minimal cross-sectional
area within the nasal cavity. The measurement is per-
formed in each nasal cavity separately.

Figure 13 Active anterior rhinomanometry

Figure 14 Acoustic rhinometry.

^ J

Techniques

1/Peak nasal inspiratory flow

Description The PNIF meter consists of a device evaluat-
ing the airflow in liter per minute passing through the
tube, and an anaesthesia mask sealing the nose and mouth
in an airtight way during nasal inspiration (Figure 12). The
anaesthesia mask should have the proper seize, i.e. not too
large preventing leakage of air, or too small compressing
the nose with impairment of nasal inspiration.

The patient is asked to blow the nose first. Then he is
instructed to exhale maximally, after which the mask is
placed over the nose and mouth with airtight seal
around the mouth and nose. The patient is then asked
to inspire forcefully through the nose with closed lips.
Lip closure is verified during the PNIF test through
inspection of lip closure through the transparent
anesthesia mask in order to prevent the generation of
false high values.

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The nasal flow is expressed in liter per minute, and
consecutive measurements are performed. Taking the
best of 3 outcomes with less than 10% variation is con-
sidered to be the best means of expression of the result
[85].

Devices Youlten peak flow meter (Clement Clark Inter-
national) attached to anesthesia mask.
Advantages - cheap and portable equipment

- assistance not required after short training session
(5 minutes)

- rapid and easy to use

- good correlation with subjective feeling of nasal
obstruction

Disadvantages - influence of lower airway function

- cooperation of patient required

- no unilateral measurement possible

- impossible in patients with alar collapse during
inspiration

2/Anterior rhinomanometry

Description Rhinomanometry provides a quantitative
measure of nasal airway resistance. In anterior rhinoma-
nometry (Figure 13), the patient is asked to blow his
nose, sits in an upright position and the pressure sen-
sing tube is placed in one nostril with total seal by tap-
ing off the nostril or inserting an olive-like device or
nozzle. The contra-lateral nostril is sealed with either
tape or olive-like device blocking off nostril. Unilateral
measurements are being performed, demonstrating any
asymmetry or abnormality in nasal airway resistance.

When the measurements are performed before and
after the application of a nasal decongestant spray, the
differences in resistance can be attributed to nasal
mucosal congestion. Data obtained after nasal deconges-
tion allow the evaluation of anatomical factors influen-
cing resistance.

Advantages - specific measurement of nasal resistance

- information on each nostril separately

- relatively ease technique

- not time-consuming

Disadvantages - relatively expensive equipment

- equipment not portable

- operator required

- impossible in case of total obstruction of one
nostril

- interference with nasal cycle

- weak correlation with subjective nasal congestion
3/Acoustic rhinometry

Description The acoustic rhinometer generates an
acoustic wave that is transmitted through a tube into
one nostril (Figure 14). The size and the pattern of the
reflected sound waves provide information on the

structure and dimensions of the nasal cavity, with the
time delay of reflections correlating with the distance
from the nostril. The conversion of echo measurements
to nasal volume requires mathematical calculations and
theoretical assumptions.

The patient sits in upright position, clears its' nose
and places the nosepiece into the nostril. The nosepiece
should fit the nostril, ensuring an airtight seal. Measure-
ments are performed during breath holding.

When the measurements are performed before and
after the application of a nasal decongestant spray, the
differences in cross-sectional diameter of the nose can
be attributed to nasal mucosal congestion. Data
obtained after nasal decongestion allow the evaluation
of anatomical factors influencing the cross-sectional dia-
meter of the nose.
Advantages - easy to use

- minimal patient cooperation

- information of each nostril separately

Disadvantages - non-physiological measure of nasal
patency

- operator required

- interference with nasal cycle

- weak correlation with subjective nasal congestion

Other techniques

* Anterior and posterior rhinoscopy Anterior rhino-
scopy allows the examiner to evaluate the anterior half
of the nasal cavity, discriminating mucosal from ana-
tomic disease. The subjective evaluation of nasal patency
by the appreciation of the endonasal lumen, anatomic
relationships and mucosal disease is the most important
diagnostic tool for the evaluation of nasal patency.

In posterior rhinoscopy, a small mirror is placed in
the oropharynx behind the soft palate, allowing the eva-
luation of the choanal openings and mucosal disease at
the nasopharynx. In experienced hands, this technique
may be helpful in the diagnosis of posterior nasal dis-
ease but its' routine use is hampered by a vomiting
reflex in a substantial portion of patients. As nasal endo-
scopy allows the full appreciation of the nasal cavity and
nasopharynx, the diagnostic role of posterior rhinoscopy
has become restricted to those cases where nasal endo-
scopy is not available or desired like in young children.

* Nasal endoscopy (Figure 8) A rigid nasal endoscope
with 0° or 30° angle is gently inserted into each nostril,
examining the inferior and middle meatus, nasopharynx,
septal anatomy and endonasal mucosal state. Due to the
limited discomfort for the patient, the possibility of
thorough examination of the nasal cavity and the infor-
mation on the mucosal condition, nasal endoscopy is
the gold standard for evaluation of nose in patients with
sinonasal disease [2].

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* Mirror test (Figure 7) Holding a cold metal spatula or
plate under the nose during expiration allows the exami-
ner to evaluation the condensation of exhaled air onto
the metal device. Specific attention is being paid to the
symmetry of the condensation or unilateral absence of
condensation. In view of the non-invasive character of
the test, the rapid, cheap and easy methodology, it can
be useful as a screening tool for evaluation of nasal
patency in children. The fact that the expiratory flow
does not correlate well with the subjective feeling of
nasal obstruction makes this test of limited diagnostic
value in the evaluation of nasal congestion.

Variability and correlation with subjective symptoms
1/Peak nasal inspiratory flow

* Variability - PNIF measures may vary from the char-
acteristics of the flow meter and mask used for analysis.

- Intra-individual variations may relate to diurnal
changes, with PNIF values being lower in the morning
and highest at dinner [85].

- Inter-individual variations may relate to subject
technique, respiratory function, and cooperation. Hor-
monal changes, microbial and environmental factors
affecting the nasal mucosal congestion like tempera-
ture and smoke, may cause changes in PNIF between
individuals.

* Correlation between PNIF and nasal obstruction
symptom A strong positive correlation has been
reported between PNIF and the subjective feeling of
nasal obstruction determined by means of question-
naires [86-88]. This positive correlation was not consis-
tently found in all studies [89,90].
2/Rhinomanometry

* Variability The nasal cycle interferes with the mea-
surement of cross-sectional diameter and data should be
interpreted in this respect.

* Correlation between rhinomanometry and nasal
obstruction Ojbective measures of nasal resistance do
not correlate well with subjective syptoms. Some studies
however show corresponding results between rhinoma-
nometry and subjective symptom scoring after inducing
(de)congestion [91,92].

3/Acoustic rhinometry

* Variability - The nasal cycle interferes with the mea-
surement of cross-sectional diameter and data should be
interpreted in this respect.

- Large inter-individual variations are present.

* Correlation between acoustic rhinometry data and
nasal obstruction In healthy individuals, there is poor
correlation between acoustic rhinometry data and sub-
jective nasal obstruction scores, whereas correlations are
better in congested subjects [93,94].

Recommendations

Depending on the specific aim of nasal patency and flow
evaluation, one may rely on different tools for the eva-
luation of nasal patency and flow. A table with clinical
use and indicitions is provided below (Table 6).

Microbiology

Rationale

The evaluation of the presence of virulent bacteria
inside the nasal and sinus cavities represents a diagnos-
tic tool in rhinosinusitis. Although there is no evidence
for benefit in establishing diagnosis or improving treat-
ment outcomes by using routine microbiological analysis
of nasal or sinus samples in uncomplicated acute or
chronic rhinitis or rhinosinusitis [2], research which was
focused during the past decade on the role of bacterial
superantigens, biofilms, response to fungal antigens,
osteitis and intracellular bacterial growth in nasal and
sinus mucosa may give rise to broader microbiological
analysis of samples from nose and sinuses, involving
new, more sensitive detection techniques. Although
detection of microbes or their products in the samples
is highly improved, problems remain with establishing
relevant microbial pathogenicity, virulence, viability on
one hand, and relevance of the detected microbes to the
development of symptoms/disease on the other hand.

Colonization versus infection

Rhinosinusitis is defined as inflammation of the nose
and sinuses and the diagnosis is based on characteristic
symptoms. The definition does not imply infection as
the etiological cause. The nasal and sinus cavities and
nasopharynx are colonized with commensal bacteria,
but also (especially in children) with those belonging to

Table 6 Tools for the evaluation of nasal patency and
flow

PNIF

Rhinomanometry

Acoustic
rhinometry

Diagnostic purposes

- unilateral disease

++

++

- correlation with

+++

+

+

syptoms

Use in children

2-6 y

+

+++

6-18 y

++

+++

Provocation studies

+++

+++

+++

Clinical trials

+++

+++

+++

Home monitoring

+++

Evaluation of effect of

+++

+++

+++

treatment

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usually pathogenic strains (like Staphyloccus aureus in
adults; Streptococcus pneumoniae or Haemophilus
influenzae in children) [95]. Such colonization does not
lead to marked inflammatory cell activation or
symptoms.

In symptomatic patients with clinical evidence of
infectious rhinosinusitis, the identified pathogen may be
considered as the cause if it is present in more than
1000 colony forming units (cfu) per ml (usually more
than 10.000 cfu. in acute rhinosinusitis), and there is an
inflammatory response of the host, proved by increased
number of leukocytes in the samples [96] .

Objectives

- to establish indications for microbiological assessment
of nasal or sinus samples in non-complicated and com-
plicated rhinitis/rhinosinusitis

- to define advantages and disadvantages of conven-
tional culture-based phenotyping of bacteria and moni-
toring antimicrobial sensitivity, serologic response
measurements and molecular techniques based on
detection of proteins or nucleic acid directly or by
amplification

- to find an evidence-based algorithm using different
microbiological sampling and detection techniques,
coupled with monitoring of the host response, and ade-
quate interpretation of the results in terms of distinguish-
ing between colonization and infection, relevance of
microbial pathogenicity and virulence for the develop-
ment of symptoms and impact of detection of microbes
and their antimicrobial sensitivity on treatment.

Technique/Instrumentation

Nasal and sinus samples for microbiological assessment
are taken as swabs, aspirates, lavages or biopsies. Moni-
toring of the local host response may be done using
cytology, biopsy or lavage, or systemically using serol-
ogy. The poor correlation between nasal/nasopharyngeal
and sinus swabs suggests that sinus sample contamina-
tion with nasal or oral cavity colonizing bacteria may
lead to misinterpretation of the microbiological results.
To obtain adequate samples, disinfection of the vestibule
is indicated if the sinus swab or lavage is taken via nasal
endoscopy or sinus puncture. Maxillary sinus samples
can be taken through inferior meatal puncture, transoral
puncture or endoscopically guided through the middle
meatus. Correlation of endoscopically taken samples
from maxillary sinuses, compared to maxillary sinus
puncture is high in most of the studies [97].

Routine bacteriological analyses of the samples are
based on cultivation on selective plates and phenotyping
and identification of gram positive, gram negative and
anaerobic bacteria. Processing and the time elapsed
from taking the samples to cultivating has an impact on

detection sensitivity, at least for some bacterial strains
(especially anaerobes). Cultivating is successful in detect-
ing only viable bacteria and counting the colony forming
units is relevant for defining significance of bacterial
growth to symptoms. Different methods of antimicrobial
sensitivity testing may be applied.

For the detection of intracellular bacteria, immunohis-
tochemistry may demonstrate a specific bacterial strain
in mucosal tissue. Detection and amplification of micro-
bial RNA and DNA has improved detection sensitivity,
but does not give information on microbial viability.
Real-time quantitative polymerase chain reaction (RT-
PCR) may give information of the number of bacteria,
but sequential samples are needed to prove viability. For
the detection of bacteria in biofilm [98], fluorescent in
situ hybridization (FISH) is usually applied, coupled
with confocal microscopy.

Sensitivity and specificity

The recovery rate in the samples of chronic maxillary
sinusitis, both aerobic and anaerobic bacteria, varied in
different studies from 45% to 92%, and is dependent on
adequate sampling, culture techniques and detecting
techniques. Although sinonasal bacteria are detected in
up to 90% of chronic rhinosinusitis patients, their role
in severity and pattern of inflammation is even less clear
than in ARS. In a study where bacteria were cultivated
in 88% of the sinus samples from patients operated for
CRS, inflammation was confirmed microscopically in
only 11% [99]. PCR may detect minute amounts of bac-
terial DNA, which may suggest extremely high sensitiv-
ity but gives no information on bacterial viability, or
impact on the inflammation. Quantitative RT-PCR may
offer information on bacterial count from small samples,
but its specificity and sensitivity depends on the primers
used for analysis. In the very few sinusitis studies com-
paring PCR with conventional microbiology, PCR was
not found to be more sensitive or specific than cultiva-
tion techniques [100].

Outcomes

There is no evidence that microbiological assessment of
nasal or sinus samples has any impact on outcomes in
rhinitis/rhinosinusitis. Although randomized double
blind placebo controlled trials indicate antibiotic treat-
ment of ARS is significantly superior to placebo [2], there
is no evidence that antibiotic treatment based on micro-
biological sampling gives better outcomes compared to
empiric antimicrobial treatment in non-complicated
acute rhinosinusitis. Thus identification of pathogens in
ARS is not indicated. European guidelines for the treat-
ment of ARS suggest that ARS non-responsive to empiri-
cal antimicrobial treatment and topical nasal steroids, as
well as complicated ARS, should be referred to an ENT

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specialist. At that time, further diagnostic procedures
including microbiology are advised [2] .

Recommendation

Microbiological assessment is not to be used routinely
in diagnosis of rhinitis/rhinosinusitis. ARS non-respon-
sive to empirical antimicrobial treatment and topical
nasal steroids should be referred to an ENT specialist,
where further diagnostic procedures, including micro-
biology, should be done.

Evaluation of Mucociliary Clearance

Rationale

In children with rhinosinusitis presenting with long-
standing and persistent anterior rhinorrhoea, one may
be interested in the evaluation of the function of the
mucociliary clearance system for diagnostic purposes
[101]. By their coordinated movement, the ciliae lining
the respiratory epithelium transport the mucus layer
with entrapped inhaled particles from the nasal cavity
towards the hypopharynx [102]. In this way, about 10
ml of mucus is transported daily from the upper air-
ways towards the hypopharynx, ultimately being swal-
lowed and cleared from the airways. Normal
mucociliary transport is essential for the maintenance
of healthy sinuses. In case of infection and/or congen-
tial dysfunction of the ciliae like in primary ciliary dys-
kinesia (PCD) [101], the mucociliary transport is
inadequately or not taken place. In PCD, lack of muco-
ciliary transport may lead to chronic rhinosinusitis and
bronchiectasis. In chronic inflammation, mucostasis,
hypoxia, microbial products, toxic inflammatory med-
iators may induce secondary ciliary changes, i.e. sec-
ondary ciliary dyskinesia (SCD), with inadaquate
mucociliary transport.

Definition

Objective evaluation of the mucociliary clearance of the
upper airways in order to quantify the proper function
of the ciliae of the respiratory epithelium lining the
upper respiratory tract.

Techniques

Mucociliary clearance time

The mucociliary transport (MCT) mechanism ensures
the clearance of entrapped particles in the mucus lining
the nasal mucosa towards the hypopharynx. Several
non-absorbable substances have been used for the eva-
luation of MCT in patients.

The saccharine test evaluates the time a patient needs
to have a sweet taste after placement of a 1-2 mm parti-
cle of saccharine on the inferior turbinate mucosa 1 cm
from the anterior end. The patient has to sit quitely
with the head bent forward and without sniffing,

coughing, sneezing, drinking or eating during the
investigation.

Alternatively, one can monitor the time needed for a
dye like methylene blue to be transported from the
mucosa of the anterior third of the nasal cavity towards
the hypopharynx. Other substances like technetium-
99m-labeled iron oxide have also been used. The MCT is
considered to be normal below 15 minutes, and should
be less than 1 hour.

As the MCT can only be measured in cooperative
patients with patent nasal cavities and in the absence of
severe mucosal disease, this test has limited diagnostic
value due to its low sensitivity and specificity. Further-
more, the test takes a long time and has a high inci-
dence of false positive and negative results [101].
Electron microscopy

Harvesting epithelial cells is performed by scraping
along the inferior and middle turbinates by the use of a
sterile cytology brush. These epithelial cells can be used
for either structural investigation of the cilia of nasal
epithelial cells with electron microscopy or for measur-
ing ciliary beat frequency [103].

In primary and secondary ciliary dysfunction, several
abnormalities can be observed in the dynein structures
of the epithelial ciliae like total/partial absence of dynein
arms, aberrant organization of the dynein arms and/or
disorientation [101]. PCD is associated with the latter
abnormalities but SCD may also present with these
structural abnormalities. Therefore, electron microscopic
evaluation of harvested epithelial cells may aid in the
diagnosis of PCD, but is not 100% sensitive nor specific.
Ciliary beat frequency measurement

Harvested epithelial cells can be evaluated for ciliary beat
frequency (CBF) and the ciliary wave form analyzed in
detail by digital high speed video imaging. The evaluation
of the frequency of the beating of cilia as well as the eva-
luation of their coordinated movement can be performed
by computerized programs using a Fast Fourrier analysis.
Normal values of CBF vary upon the methodology used,
the age of the patient, and the culture conditions. The
demonstration of normal CBF and beat pattern excludes
the diagnosis of PCD.
Ciliogenesis in vitro

The evaluation of ciliogenesis in vitro constitutes the gold
standard for diagnosis of PCD, allowing the differentiation
between primary and secondary ciliary dyskinesia. A
biopsy of the nasal mucosa is taken, and nasal epithelial
cells are dissociated by enzymatic digestion and incubated
for 6 to 8 weeks until cilia reappear on the apical side of
the epithelial cells. The new cilia can be evaluated for their
electron microscopic structure and coordinated activity. In
PCD patients, no ciliogenesis takes place whereas patients
with ciliary dysfunction due to infection/inflammation pre-
sent with properly functioning ciliae after ciliogenesis.

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Recommendations

No ideal test is available for the diagnosis of PCD. In
case of suspicion of PCD in a patient with rhinosinusitis
since birth, familial history of PCD and associated fea-
tures of Kartagener syndrome, i.e. situs inversus and
infertility, one should consider diagnostic tests of ciliary
function by evaluation of CBF, electron microscopic eva-
luation of the dynein arms of the cilia, and/or evaluation
of the cilia after ciliogenesis in vitro. As these techni-
ques are not available in routine ENT practice, one may
rely on measuring nasal NO levels as low NO levels
have been associated with PCD and therefore represent
a good screening tool for PCD (see chapter on NO
measurement).

Blood and Additional Tests

Rationale

Blood analysis may confirm or refute the definite diag-
nosis in specific clinical conditions.

Rhinitis

Blood analyses including tests for allergen-specific IgE
have been dealt with in the section on allergy testing. In
severe non-infectious, non-allergic rhinitis, one may con-
sider full blood count, including eosinophils, thyroid func-
tion, thyroid auto- antibodies, anti- nuclear antibodies,
extractable nuclear antibodies (anti- Ro and anti-La are
usually positive in Sjogren's syndrome), pregnancy test or
tests for drugs of addiction on urine. Sjogren's syndrome
(SjS) is a relatively common autoimmune disease charac-
terized by oral and ocular dryness. Patients may present to
the rhinitis clinic with symptoms of nasal obstruction, dry-
ness or cough. There is an increasing need for simple, sen-
sitive and rapid technologies for the diagnosis of SjS and
other autoimmune diseases. A quick version of luciferase
immunoprecipitation systems (QLIPS) can now be used to
produce a rapid, specific and quantitative test to detect
auto-antibodies associated with SjS. Ro52 was the most
informative with antibody titers in the Ro52-seropositive
SjS samples approximately 1000 times higher than in
healthy controls. Validation of the anti-Ro52 QLIPS test
showed 66% sensitivity and 100% specificity and has the
potential to be adapted for point-of-care evaluation of
patients with SjS and other rheumatologic diseases [104].
The need for biopsy looking for lymphocytic infiltration of
salivary glands should be reduced and in any case is inac-
curate in elderly patients [105].

In case of rhinorrhoea only, especially if unilateral,
beta2-transferrin should be measured in nasal secretions.
If present, the secretions are cerebro-spinal fluid and
reveal a skull base defect. Beta-2 transferrin is a carbohy-
drate-free (desialated) isoform of transferrin, which is
almost exclusively found in the CSF- blood or nasal
secretion does not disturb the test. Beta-2 transferrin is

not present in blood, nasal mucus, tears or mucosal dis-
charge. This protein was first described in 1979. Intense
research over the last decade has validated its characteris-
tics and value in clinical use as a specific CSF marker
[106]. Beta-2 transferrin was reported to have a sensitiv-
ity of near 100% and a specificity of about 95% in a large
retrospective study. Detection of glucose in the nasal
sample fluid using Glucostix strips has been a traditional
method for detection of the presence of CSF in nasal and
ear discharge. Glucose detection using Glucostix test
strips is not recommended as a confirmatory test due to
its lack of specificity and sensitivity. Interpretation of the
results is confounded by various factors such as contami-
nation from glucose-containing fluid (tears, nasal mucus,
blood in nasal mucus) or relatively low CSF glucose levels
(meningitis). Studies have shown that glucose can be
detected in airways secretions from people with diabetes
mellitus, stress hyperglycaemia and viral colds.

Rhinosinusitis without nasal polyps

Depending on the clinical history and examination, con-
sider the following analyses:

* full blood count including differential white cell
count, ESR and/or C Reactive Protein,

* evaluation of renal, liver and thyroid function

* humoral immunity markers: immunoglobulins, IgG
subclasses, specific antibody levels to tetanus, haemophi-
lus, pneumococcus and response to immunization if
low,

* cellular immunity markers: T and B cell numbers
and ratios

* HIV status.

* Angiotensin converting enzyme (ACE) is usually up-
regulated in macrophage activation in diseases such as
sarcoidosis and tuberculosis. Of note, the following diag-
nostic tests aided to diagnose ocular sarcoidosis [107]:
negative tuberculin skin test in a BCG-vaccinated patient
or in a patient having had a positive tuberculin skin test
previously, elevated serum angiotensin converting
enzyme (ACE) levels and/or elevated serum lysozyme,
chest x-ray revealing bilateral hilar lymphadenopathy
(BHL), abnormal liver enzyme tests, and chest CT scan
in patients with a negative chest x-ray result.

* c-ANCAs (anti- neutrophil cytoplasmic antibodies)
are raised in Wegener's granulomatosis, in 60% of
patients where upper respiratory tract alone is involved.

Rhinosinusitis with nasal polyps

Some specific pathologic entities should be considered
in severe nasal polyp disease and require additional
investigations.

1/Churg Strauss syndrome(CSS)

ANCAs are present in approximately 40% of patients
with CSS. A pANCA pattern with specificity for MPO is

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found in most ANCA-positive patients. ANCA positivity
is mainly associated with glomerular and alveolar capil-
laritis [108].

Antineutrophil cytoplasmic antibodies (ANCA) are
predominantly IgG autoantibodies directed against con-
stituents of primary lysosome granules of neutrophils
and monocytes. Several antigenic targets exist: those
ANCA directed to proteinase 3 or myeloperoxidase are
clinically relevan. The importance of other ANCA
remains unknown. Both are strongly associated with
small vessel vasculitides, including Wegener's granulo-
matosis, microscopic polyangiitis, and Churg-Strauss
syndrome, and the localised forms of these diseases (eg,
pauci-immune necrotising and crescentic glomerulone-
phritis). ANCA is a useful serological test to assist in
diagnosis of small-vessel vasculitides. 85-95% of patients
with Wegener's granulomatosis, microscopic polyangii-
tis, and pauci-immune necrotising and crescentic glo-
merulonephritis have serum ANCA [109]. Besides their
diagnostic potential, ANCA might be valuable in disease
monitoring, although the ESR is quicker.

Recent data seem to confirm the long-disputed patho-
genic role of these antibodies: myeloperoxidase-ANCA
are directly involved in the pathogenesis of necrotizing
vasculitis. This is less clear for proteinase 3-ANCA,
markers for Wegener's granulomatosis. Complementary
proteinase 3, a peptide translated from the antisense
DNA strand of proteinase 3 and homologous to several
microbial peptides, may be involved in induction of pro-
teinase 3-antineutrophil cytoplasmic autoantibodies.

A strategy based on screening for ANCA with ELISA
or fluoroenzymeimmunoassay (FEIA) without prior
indirect immunofluorescence (IIF) is a valuable alterna-
tive to screening with IIF and confirming with ELISA or
FEIA.

Cocaine-induced midline destructive lesions unfortu-
nately have a high prevalence of cytoplasmic antineutro-
phil cytoplasmic antibodies, limiting this test's
usefulness in distinguishing this disorder from Wege-
ner's granulomatosis [110].
2/Aspirin sensitivity

The aspirin provocation test, considered to be the gold
standard in the diagnosis of aspirin sensitivity, may be
associated with severe adverse reactions; thus, alternative
procedures with a higher safety profile are highly desir-
able. Although the cellular antigen stimulation test
(CAST) has been proposed as an alternative a recent
study using CAST to measure cys LTs pre and post
challenge showed that although the leukocytes of
patients with aspirin sensitivity produce higher amounts
of Cys-LTs as measured by CAST the assay had a sensi-
tivity of 25%, a specificity of 92.3%, and positive and
negative predictive values of 28.7% and 90.7%, respec-
tively. The low sensitivity and predictive values limit the

clinical usefulness of this test in the diagnosis of aspirin
sensitivity [111].
3/Fungal sinusitis

Fungal spores are continuously inhaled and deposited
on the airway mucosa, both in healthy persons as well
as in patients with CRS. Five forms of fungal disease
affecting the nose and paranasal sinuses have been
recognized [112]:

(1) acute invasive fungal rhinosinusitis (including rhi-
nocerebral mucormycosis),

(2) chronic invasive fungal rhinosinusitis,

(3) granulomatous invasive fungal rhinosinusitis,

(4) fungal ball (mycetoma), and

(5) non-invasive (allergic) fungal rhinosinusitis.
There are several potential deficits in the innate and

potentially also acquired immunity of CRS patients that
might reduce or change their ability to react to fungi.
There are not many arguments to suggest a causative
role for fungi in CRS with or without nasal polyps.
However, due to the intrinsic or induced change in
immunity of CRS patients, fungi might have a disease-
modifying role.
4/Primary ciliary dyskinesia

Congenital dysfunction of the mucociliary transport sys-
tem, called primary ciliary dyskinesia (PCD) is a rare heri-
ditary condition, associated with dextrocardia and
infertiliy. The discrimination between PCD and secondary
dysfunction of the cilia due to microbial or environmental
agents, is crucial for the diagnosis. Several diagnostic tools
are available. Determination of the mucociliary clearance
time is a non-invasive, cheap and rapid diagnostic tool,
with relatively low sensitivity and specificity. Nasal NO is
reported to be very low in patients with PCD [113] in con-
trast to CRS, NP and other nasal inflammatory conditions.
Therefore, nasal NO measurement represents a valuable
screening tool for PCD. Electron microscopic evaluation
of the epithelial cilia may provide additional hints for the
diagnosis without being 100% specific or sensitive [114].
The definite proof of PCD comes from epithelial cell cul-
tures and of ciliogenesis in vitro [115]. However, the time-
consuming and costly nature of this investigation limits
its' use as a screening tool.
5/Cystic Fibrosis (CF)

The diagnosis of CF is suspected in case of severe CRS
with NP and thickened secretions, hypoplasia of the para-
nasal sinuses, in association with recurrent broncho-pul-
monary infections. CF is an autosomal recessive disease
caused by mutations in the the CF transmembrane con-
ductance regulator (CFTR) gene that results in abnormal
viscous mucoid secretions in multiple organs and with
rhinosinusitis as one of the clinical features beside endo-
bronchial infections and pancreatic insufficiency.

Blood analysis for CFTR gene mutations may demon-
strate homozygote and heterozygote gene mutations in a

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subgroup of CF patients [116]. CT scans of the parana-
sal sinuses may show features associated with CF: hypo-
plasia of the frontal and/or sphenoidal sinuses, full
opacification of most sinonasal cavities, and pseudomu-
cocoeles in the maxillary sinuses with medialization of
the lateral nasal wall.

The sweat test remains the gold standard for diagnosis
of CF, as it is non-invasive, cheap and painless, with
high sensitivity and specificity.

Recommendations

* Blood analysis may be an alternative for skin prick test
in patients suspect of allergic rhinitis.

* Specific patients with non-allergic, non-infectious
rhinitis may require the following analyses: full blood
count, including eosinophils, thyroid function, thyroid
auto-antibodies, anti- nuclear antibodies, extractable
nuclear antibodies in Sjogren's syndrome, pregnancy test
or tests for drugs of addiction on urine.

* In specific cases of rhinosinusitis without NP the fol-
lowing analyses are recommended:

* full blood count including differential white cell
count, ESR and/ or C Reactive Protein,

* evaluation of renal, liver and thyroid function

* humoral immunity markers: immunoglobulins, IgG
subclasses, specific antibody levels to tetanus, haemophi-
lus, pneumococcus and response to immunization if
low,

* cellular immunity markers: T and B cell numbers
and ratios

* HIV status.

* Angiotensin converting enzyme (ACE)

* ANCA

Imaging in Rhinology

Rationale

Imaging of the nose and sino-nasal cavity is used as an
objective diagnostic tool in establishing the diagnosis
and in staging the severity of rhinosinusitis (RS) and
nasal polyposis (NP). The diagnosis of RS with/without
NP is based on the presence of characteristic clinical
symptoms, which are confirmed by either nasal endo-
scopy or radiographic imaging [2]. Computerized tomo-
graphy (CT) scans provide substantial information about
paranasal sinus anatomy and are mandatory for safe
endoscopic sinus surgery. Unlike standard X-ray and
ultrasonography (USG), CT scans of the sino-nasal cav-
ity and magnetic resonance imaging [117] provide objec-
tive information on the extent of sinus disease and are
the most frequently used objective tools in staging of
severity of the disease (with the exception of endoscopic
staging of polyp size). For evaluation of the bony anat-
omy and discrimination of the sino-nasal cavities.

Objectives

The aims of radiologic imaging are the demonstration of
the source of individual sino-nasal symptoms, the extent
of the sinonasal disease, the relation of the sinonasal
problem with surrounding structures and the evaluation
of the sinonasal anatomy prior to sinus surgery.

Techniques

Plain film radiographs in standard projections (Caldwell
and Waters frontal views and Rhese oblique view) provide
little information on disease extent and no information on
sinus anatomy. They do provide some information on the
size of the sinuses and air content in the maxillary and
frontal sinuses, but discriminate poorly between bone,
mucosa and secretion compared to CT or MRI and may
be misleading in diagnosis, and dangerous in surgery.
Therefore, plain X-ray radiographs are not advised in rou-
tine rhinology clinic. In children with clinical suspicion of
adenoid hypertrophy being responsible for nasal obstruc-
tion, lateral plain X-ray images (Figure 15) may show the
adenoid hypertrophy and be of help in the therapeutic
approach in these children.

Following the introduction of CT scans in the 1970s and
the concepts of functional endoscopic sinus surgery
(FESS) in the 1980s, CT scanning has become the most
important imaging modality and helped the development
of endoscopic surgery of the sinuses and skull base. The
new multi-detector CT (MDCT or MSCT) scanners (4th
generation CT scanners) have achieved very short radia-
tion exposure time, taking scans in one cycle, using spiral

Figure 15 Plain X ray of skull allowing the evaluation of the
adenoid volume in relation to the nasopharyngeal airway
passage.

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mode, instead of two projections used in previous genera-
tions, which was more time consuming, and uncomforta-
ble for some patients. They also enable multi-planar
reconstructions, even in curved planes, like a reconstruc-
tion of orthopantomography of the upper jaw and allow
precise coronal, axial, sagittal and various 3D reconstruc-
tions as well as virtual endoscopy. The MDCT scanning
should be done at 3 mm contiguous slices or less through-
out the 3 planar scans using both wide («bone») and nar-
row («soft-tissue») window settings. Such reconstructions
are useful in surgical planning, but are not needed for sta-
ging. Low-dose protocols should be applied, taking into
account the potential pathology. Although new software
packages enable 3D reconstructions and virtual endo-
scopy, besides being time consuming, such images cannot
replace surgeons' preoperative analysis of the scans in 3
projections.

Coronal sections have been the most requested plane
on CT imaging of the nose and sinuses as this closest
resembles the surgical anatomy encountered in endo-
scopic sinus surgery, presenting ostio-meatal complex
(unit) and relationship between sinuses, orbit, and skull
base (Figure 16). Axial sections may be required to
visualize the anterior and posterior walls of the sinuses.
Reconstruction of MSCT scans in coronal, axial and
sagittal planes, enable excellent surgical planning
nowadays.

Although more time consuming and costly, the use of
MRI is recommended in patients with complicated inflam-
matory sinus disease extending beyond the boundaries of
the sinonasal cavities and/or in patients with suspected
neoplasms. Tl, T2 and STIR protocols are used, enabling
superior resolution to CT on the interfaces between

mucosal lining, dura, fat and secretions, but CT and MR
present complementary techniques for imaging in these
unique circumstances. Contrast-enhanced high resolution
SE axial and coronal Tl-WI further differentiate soft tissue
structures and intracranial and/or intra-orbital extension
of pathology can be better demonstrated in this manner.
Although there is no ionizing radiation, allowing MRI to
be repeated, certain contraindications for its use should be
considered such as metal objects, prosthesis and implants,
e.g. cardiac pacemaker, implanted cardiac defibrillator,
aneurysm clips, carotid artery vascular clamp, neurostimu-
lator, insulin or infusion pump, implanted drug infusion
device, bone growth/fusion stimulator, cochlear, otologic,
or ear implant. The duration and methodology of MRI
can cause claustrophobia.

Ultrasonography of the paranasal sinuses is easily
available, cheap and quick, with no irradiation or dis-
comfort involved. Ultrasonography offers an opportunity
for repetitive examination, which might be important
for the follow-up in evolution of acute rhinosinusitis.
Sensitivities have been reported from 29% to 100% and
specificities from 55% to 99%, but limited to analysis of
maxillary and frontal sinuses. However, it provides little
information on disease extent.

Sensitivity and specificity

The diagnosis of rhinosinusitis is largely based on the
patient's history, with radiologic imaging confirming the
clinical diagnosis of RS. It is impossible to differentiate
between acute and chronic rhinosinusitis based on ima-
ging. CT scan is not indicated as a diagnostic procedure
in acute rhinosinusitis, except when a complication is
suspected or recurrent rhinosinusitis is not responsive to

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treatment. As CT and MRI are sensitive enough to detect
changes in the paranasal sinuses of asymptomatic indivi-
duals, it is also important to realize that a significant por-
tion of asymptomatic patients show abnormalities on CT
scans [2].

When comparing concordance between endoscopy and
CT staging in rhinosinusitis, the correlation was 65% for
positive and 71% for negative results [118]. The various
staging systems have been used to judge the severity of
rhinosinusitis based on extent of the inflammatory dis-
ease within the paranasal sinuses. Most of the CT staging
systems tried to divide severity into 4 grades or 4 stages
(Kennedy, Levine and May, Friedman, Harvard). How-
ever, validation studies of the different staging systems
have shown that a simple scoring system such as the
Lund-Mackay score would better quantify severity of the
disease, although no system currently available allows
clinicians to judge the evolution of this disease or to indi-
cate prognosis [119]. The Lund Mackay system is based
on scoring each sinus with 0-2 points (0- no pathology, 1
point any partial opacity, 2 points- total opacity), giving a
score of 0-12 per side. However, even this system does
not result in significant correlation with symptom sever-
ity scores. Normal Lund-Mackay score for adults is 4.26
(95% CI, 3.43 to 5.10) [120] and for children it is 2,81
(95% confidence interval, 2.40 to 3.22), with only 19,3%
having a score of 0 [119].

The accuracy of CT in the diagnosis of CRS was tested,
comparing CT scores with histopathologic grade of
inflammation and compared to a control group without
rhinosinusitis utilizing well designed criteria. By using the
ROC method, the sensitivity of CT was found to be 94%
and specificity 41% using Lund score cut-off value for RS
greater than 2, while putting it at the level of incidental
Lund scores (above 4) increased specificity to 59%. Using
the same method in pediatric rhinosinusitis, the same
author found, using a Lund score cut off of five to repre-
sent true disease, sensitivity of the CT at 86% and specifi-
city 85%. Lund scores of two or less have an excellent
negative predictive value, and Lund scores of five or more
have an excellent positive predictive value, strongly indi-
cating true disease.

Plain sinus radiographs have shown poor sensitivity
and specificity, so that even low irradiation does not
justify its' use. In the studies comparing plain sinus
radiographs with sinus CT scans, the sensitivity of plain
film radiography ranged from 36.7 to 66.4% depending
on localization, while specificity was high (90% and
over) with the exception of the maxillary sinus (82%) in
one study. The other study has confirmed better match-
ing of the CT scans with plain sinus radiographs for
maxillary sinusitis (78%), but only 52% for the ethmoids
[121].

Outcomes

CT scans remain the gold standard for diagnosis of rhi-
nosinusitis and for pre-operative evaluation of the sino-
nasal anatomy. CT scoring has been used to show
improvement in different treatment studies in ARS and
CRS but the correlation of the symptom improvement
rate with CT score improvement rate was often not sig-
nificant. Due to the radiation dose, CT score improve-
ment cannot be used as an outcome measure for ethical
reasons. As a good correlation between scores on CT
and MRI has been shown, MRI might be a more appro-
priate imaging outcome. MRI is useful for diagnosis and
follow-up of patients with benign (eg inverted papil-
loma) or malignant (eg adenocarcinoma) sinonasal
pathology.

Recommendations

There is no evidence to support the use of imaging in
uncomplicated acute rhinosinusitis. In contrast to ARS
where CT scans are not mandatory for diagnosis, CT
scans may confirm the clinical diagnosis of CRS. The
use of CT scans in 3-dimensional views are highly
recommended as a roadmap for endoscopic sinus sur-
gery in order to define specific anatomic relations in the
individual patient.

Plain sinus radiographs have low informative value as
is the case for ultrasonography, both being characterized
by low sensitivity, but somewhat better specificity in
maxillary and frontal sinusitis.

Diagnosis of Occupational Rhinitis

History

The diagnosis of occupational rhinitis (OR) is based on
very careful and detailed medical history and history of
exposure conditions at work [122]. The purpose of the
clinical history is to confirm the existence of rhinitis
and to evaluate it's the link to work. Because often the
diagnosis of OR have substantial financial and work-
related consequences, the relationship with the work
exposure needs to be ascertained with provocation tests
[122]. A distinction is made on rhinitis caused by agents
in the working environment, i.e. OR, and rhinitis exacer-
bated by the work environment, i.e. work-exacerbated
rhinitis (Figure 17).

Symptoms and medical history

The medical history should include the information
about the exposures at work and their potential capacity
to cause sensitization or irritate the nasal mucosa. This
information is normally asked from the employer. Any
chemicals and proteins that can be sensitizers or irri-
tants should be recorded. How they are used and what
is the protective measure at work should be recorded.

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Work-related rhinitis

Rhinitis
caused
by work

Occupational
Rhinitis
(OR)

Rhinitis
exacerbated
by work

Work-
Exacerbated
Rhinitis (WER)

1

* Allergic OR (with latency period):

• IgE-mediated

• Non-lgE-mediated

* Non-allergic OR (without latency):

• Single exposure: RUDS

• Multiple exposures: Irritant-
induced OR

• Corrosive rhinitis

Figure 17 Occupational vs work-exacerbated rhinitis.

Patients should be asked about the time of the exposure
starting, how long it has lasted and what is the exposure
level and time of exposure daily and weekly. The rela-
tion of the symptoms to work and the alleviation of
them when away from the work are important clues to
diagnose OR. The typical symptoms are rhinorrhoea,
sniffing, nasal stuffiness and nasal itch as in any allergic
rhinitis but even one of these symptoms can be present,
especially if the exposure has continue long. Often nasal
stuffiness is the main symptom and rhinorrhoea and
sneezing often subsides when the exposure continues
longer timer. Patients can have hoarseness and cough-
ing, even asthma symptoms during the work hours as
well. It is relevant to ask when the patient first time was
treated by physician because of rhinitis symptoms and
also exclude other reasons for rhinitis like sinusitis and
seasonal or perennial allergy.

Examinations and immunological tests

A routine ENT examination including nasal endoscopy
should be performed. Skin prick test and/or specific IgE
tests for common aeroallergens and work related aller-
gens and chemicals are mandatory. Common aeroaller-
gens are tested to exclude their role and show if the

patient is atopic already. It is know that atopic patients
have more symptoms and are easier sensitized to new
allergens. SPT are considered to be positive when the
mean wheal diameter is exceeds 3 mm (area > 7 mm).
Positive immunological test may appear in a substantial
proportion of exposed asymptomatic individuals. On the
other hand, a negative test result makes the diagnosis of
OR unlikely, provided that appropriate allergens have
been tested. The main limitation of immunological tests
in the investigation of occupational allergy results from
the lack of standardized, commercially available extracts,
especially low molecular weight agents [122].

If lower airway symptoms like cough, wheezing, dys-
pnoea or diminished ability for physical strain exist,
additional spirometry and other examinations to exclude
asthma are needed. In addition, use of any medication
and other airway or systemic diseases possibly relating
to the symptoms should be recorded.

Nasal and inhalation challenge tests

Both nasal as well as bronchial challenge tests can be
applied for the diagnosis of OR (Figure 18). Nasal chal-
lenge tests are the standard diagnostic tool to confirm
the causative role of a specific agent in the development
of rhinitis symptoms. Nasal provocation testing repre-
sents an essential tool in the diagnosis of allergic OR
but needs to be evaluated in the context of the medical
and work history and sensitization stat [123]. Several
methods of exposure of one or both nostrils are being
reported: throw dropping or spraying and solid agents
by direct application, by special devices or by sniffing.
Inhalation challenge (IC) tests are rarely reported to be
used in the diagnosis of OR, but represent a valuable
method in the simultaneous evaluation of patients with
both lower and upper airways symptoms [124]. Even IC
is resource-intensive methodology, the evaluation of
nasal and bronchial reactions together save time and
expenses compared to organization of multiple indivi-
dual challenges [125].

There are no uniformly accepted criteria for the eva-
luation of nasal challenge reactions. In addition the test
can be performed either unilaterally or bilaterally. Var-
ious symptoms and findings scoring criteria based on
clinical findings or patient symptoms have been tradi-
tionally used as the main criteria of the positivity of
nasal challenge reactions. For example the sneeze count,
inspected nasal blockage (congestion), itching or burn-
ing of the nose, palate or throat and lacrimation have
been used 48 or symptom score of nasal itching, sneez-
ing, and rhinoscopic nasal obstruction, rhinorrhea, and
mucosal oedema [126]. In addition to the scoring cri-
teria objective instruments like acoustic rhinometry and
anterior rhinomanometry are used. Minimum cross-sec-
tional area of the nose [127] and nasal volume from 2-5

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Clinical and occupational history
Nasal examination

Immunological tests

(skin-prick tests and/or specific IgE antibodies)

Not available

(e.g. LMW agents)

Available

(e.g. HMW agents)

Negative

According to
clinical history

Positive

Nasal provocation test in the
laboratory

According to
required level
of diagnostic
conf clence

DEFINITE
OCCUPATIONAL
RHINITIS

Negative

Not feasible

According to
clinical history

PROBABLE
OCCUPATIONAL
RHINITIS

Workplace assessment of:

Symptoms
Nasal patency
Nasal inflammation
Nonspecific hyperresponsiveness

Positive

Negative

NON-OCCUPATIONAL
RHINITIS

Figure 18 Diagnostic algorithm for occupational rhinitis.

cm depth have been used for evaluation of nasal mucosa
reactions [128]. In addition nasal peak inspiratory flow
as well as optical rhinometry and rhinostereometry have
been introduced for the evaluation of nasal provocation
results. Measurement of secretion has been introduced
as one objective and relevant measurement of nasal pro-
vocation test, and that in a unilateral test it has shown
to be slightly superior to acoustic rhinometry and rhino-
manometry [129]. Sham provocation tests should be
used to confirm the positive reaction with occupational
exposure and exclude general nasal hyperreactivity.

Recommendations

The diagnosis of occupational rhinitis is based on the
patients' history. Allergic OR should be dealt with diag-
nostically like any other allergic rhinitis, whereas non-
allergic occupational disease requires more specific
attention. In case of important socio-economic impact
of the diagnosis of OR, the diagnosis can be confirmed
by provocation tests that need to be performed in a
standardized way involving subjective as well as objec-
tive evaluation of inflammation.

Future Tools

We are dealing with complex diseases in Rhinology and
need a systems biological approach that could spell the
end of clinical and basic science as independent research
fields. Why do patients with the same sensitization pre-
sent with such a variety of symptoms or why are some
patients sensitized only for house dust mite or grass pol-
len, while yet others are sensitized for both? Are we look-
ing at a single disease with different levels of expression
or should we consider that these individuals suffer from
similar, yet different diseases? There are a large number
of chronic rhinosinusitis patients who may all suffer from
the same disease or from different disease modalities that
have a similar symptomatology. Clinical or basic scientific
conclusions drawn from an inhomogeneous group of
patients may misinterpret the molecular mechanisms or
the clinical symptomatology of the disease under
investigation.

From a clinical point of view it may seem that the
healthy individual is probably the least interesting to
study except as a control in all good studies, but hardly
ever as the prime focus of research. This practice needs

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to be re-examined. It is very important to understand the
normal healthy response and compare this response to
the aberrant response in an allergic individual. In the
case of the immunologic response this concept would
lead to a number of states of the immune system that
would also depend on whether we look at a healthy or a
diseased individual. Moreover, these differences would
not only be there at the tissue level, but also at the pro-
tein expression pattern level in individual cells.

We therefore need to re-evaluate our research tools. In
hypothesis-driven research we investigate the role of one
or a limited number of players on a complex disease pro-
cess, limiting our powers of observation. New analysis
tools may allow us to analyse a disease in a single indivi-
dual. However this will mean that we need to collect
many data points for a single patient, in contrasts to the
present custom of collecting a few data points for many
patients. Fortunately, any of the "omics" techniques
(genomics, transcriptomics, or proteomics) allow this
approach.

Genetics, transcriptomics, and proteomics are tradi-
tionally seen as three complementary and equivalent
research fields in that each addresses a different part of
the information highway. An important realization is that
both the diseased and the healthy state is a complex
interplay between a large number of factors that influ-
ence each other. The transition from healthy to diseased
state could affect only a small proportion of the factors
defining the healthy state, but current data suggest that
differences are rather large. This is most clearly seen
when the healthy and diseased states are compared at the
tissue level. The question arises how the two states can
change from one to the other. Due to the inherent pre-
sence of negative and positive feedback loops, a network
is often very resistant to change. It may accommodate
small changes, but large deviations from equilibrium may
require more than one defect in network components.
There are likely to be multiple different combinations of
defects yielding a similar change from baseline. When a
disease is studied by looking for defects on a genome
wide level, we might run into the problem that although
we study a single disease that the multitude of different
combination of factors involved would introduce such a
large mix that statistics may not be able to identify indivi-
dual factors. At the moment it would seem that (A) a lot
of factors have been reported to be affected and that (B)
none of the factors are specific for the disease and are at
best found enriched in the diseased population. Although
impractical (one would need to include too many well-
defined patients), the different studies into genetics
should also consider previously collected data on other
genes.

This particular problem does not arise when proteomics
or transcriptomics is used, as the expression pattern will

define the disease even though the underlying reasons for
the change into the diseased state might be different. This
last point is again one of the two biggest problems. The
disease can be well-described using proteomics and tran-
scriptomics, but now we will find it hard to define the
mutation responsible for the diseased state. A concept that
has not yet been put to the test would combine the best of
both worlds; use transcriptomics and proteomics to define
the disease and then focus the mutation analysis specifi-
cally on the genes/proteins that are found affected. This
would reduce the number of genes to screen down to a
more manageable level, so that perhaps even interactions
between mutations in different genes would become feasi-
ble. A second down-side of transcriptomics and proteo-
mics is in the selection of material that will be studied.
Given the concept of systems biology it would be tempting
to investigate diseased versus healthy tissue samples, but
this comes at a price. Firstly, it is not always clear what
needs to be compared. In the case of chronic rhinosinusitis
one might question if healthy turbinate would be useful in
the comparison with nasal polyps as, firstly, they are not
identical structures and, secondly, they are found at differ-
ent locations within the nasal cavity. Even when compar-
able tissues can be found (eg. turbinates of allergic and
healthy individuals) transcriptomics and proteomics would
also measure differences in tissue composition. Techni-
ques that would take this into account are struggling to
discriminate between changes in expression in a given cell
and difference caused by differences in numbers of these
cells between diseased and healthy tissues. Focusing on a
single cell type would eliminate this problem, at the cost
of a less comprehensive overview of the systems biology
and the unknown consequences on expression patterns in
cells that have been isolated and as a consequence have
been taken out of their normal tissue environment.

Dealing with complex data

After all the clinical and molecular data have been col-
lected, there is a long list of matters that differ between a
healthy and a diseased individual. We could analyze the
items on the top of the list that have changed the most in
more detail, but it would seem to defeat the point of col-
lecting all data in the first place. We do not know whether
items that change the most, are also the most important
in the disease process. A number of analytical tools exists
that can help our understanding [130]. The first tool helps
us to define what causes the variation in all the data we
have collected. Principal component analysis lists these
causes in order of their contribution. An example from
our own epithelial work in allergic rhinitis shows that the
diseased state (the difference between healthy and allergic)
is the most important component, followed by differences
between healthy individuals [131]. This reminds us again
that we are all clearly different, but also shows that the

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allergic individuals resemble each other more strongly.
Interestingly, this approach could also be used as a diag-
nostic tool as the location in the plot could identify the
individual as either diseased or healthy. Moreover should
we have labelled an individual incorrectly, this would not
have affected the outcome as individuals are separate data
points in the graph and need not to be grouped before-
hand for this analysis.

The second tool is network analysis showing how the
factors we have identified interact together. Using data
from literature it either groups the items on the basis of
previously reported physical interaction or on reported
effects of one item on the expression pattern of another.
Again from our own work on the effect of house dust
mite allergen on nasal epithelial cells we derive a tran-
scription regulation model [131,132]. This can be com-
bined with a clustering tool that describes the expression
behaviour of genes. At this last level we can think of
interfering with the disease as the type of expression pro-
file in a cluster might represent an essential behaviour to
deal with the diseased state. Understanding the regula-
tion of such a cluster of the transcription factor level, the
signal transduction level, or the recently identified micro
RNA level, could lead to the identification of new targets
for treatment.

Concluding Recommendations

In the following table (table 7), recommendations for each
diagnostic tool which has been revised are summarized.

Summary

We need to merge all available data into one big model
of reality. The second important issue is that we need to
be very strict in our patient selection as failure to do so
will yield confusing data or alternatively focus on a sin-
gle individual as if he or she has unique disease, and
then try to cure this disease for this individual. The uni-
fication of clinical and basic scientific research has
started and will be with us for some time to come.

Appendix

Different Tools to Assess Sense of Smell

University of Pennsylvania Smell Identification Test (UPSIT)

Method: The UPSIT test is a rapid and easy-to-adminis-
ter method to quantitatively assess human olfactory func-
tion [133]. The UPSIT shows a high test-retest reliability
and scores on this test are strongly correlated with the
detection threshold for phenyl ethyl alcohol in the same
individuals. When the UPSIT is administered in the stan-
dardized manner, clinical subjects show a high degree of
uniformity in UPSIT performance when tested in differ-
ent laboratories. The 40-odorant UPSIT is used in over
1500 clinics and laboratories throughout the United
States, Canada, South America, and Europe, and has

been administered to nearly 200,000 people since its
development in the early 1980s. Hundreds of published
papers have employed this test in academic, clinical, and
industrial settings. A particular strength of this test is
that it provides an olfactory diagnosis based on compar-
ing the patient's test score with normative data, providing
a percentile score of an individual relative to his or her
age-matched normal group. Furthermore, a clinician can
distinguish patients with a normal sense of smell ("nor-
mosmia") from those with different levels of reduction
("mild, moderate and severe microsmia") or loss ("anos-
mia"). The test can also distinguish "probable malin-
gerers" from those with true olfactory deficits.

The test consists of four booklets, each containing 10
odorants with one odorant per page. The stimuli are
embedded in 10-50 (mu) diameter plastic microcapsules
on brown strips at the bottom of each page. Above each
odorant strip is a multiple-choice question with four
alternative words to describe the odour. The subject was
asked to release the odorant by rubbing the brown-strip
with the tip of a pencil and to indicate which of four
words best describes the odour. Thus each subject
received a score out of 40 possible correct answers.

Test-time: 15 min.

Test-retest reliability: r: 0.981.

Country: USA
Conneticut Chemosensory Clinical Research Center Test
(CCCRC)

Method: The CCRC consists of two tests of olfactory
performance [134]: an odour identification task and the
determination of the n-butanol threshold. Presentation
of odorants for threshold testing is performed by means
of a plastic squeeze bottles while odour identification is
assessed by means of sniff bottles (bottles made of
glass). The highest concentration of butanol in the series
was 4% in water; 11 successive dilutions were estab-
lished as a geometric series dilution ratio of 1:3. Testing
was performed with the concentrations in ascending ser-
ies using a two-alternative, forced choice paradigm by
which patients have to identify the odorant containing
bottle after both odorant and blank have been adminis-
tered (double-alternative, forced choice paradigm). The
threshold was defined as the concentration at which
subjects correctly identify n-butanol in five successive
trials. The odour identification task employed eight
items (baby powder, chocolate, cinnamon, coffee, moth-
balls, peanut butter, ivory soap and Vicks Vaposteam).
Patients were given a list with 16 terms comprising
eight terms describing the items used in the test and
eight items describing other common items. All odor-
ants were handled most carefully; the experimenters
always wore deodorized disposable cotton gloves. Mea-
surements were performed in quiet, well-ventilated
rooms.

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Table 7 Recommendations for diagnostic tools in rhinoloy

AIMS

METHODS
INSTRUMENTS

RECOMMENDATIONS

HISTORY

Evaluation of

* patients' symptoms and symptom

strvtrl I ly

* co-morbidities and general medical
condition

* medical/surgical history

* exposure to allergens/irritants

* cigarette smoke

* Persona
communication

* f~li loctirin np i rcic:
^uctjjLIUI ii I a 1 1 ci

Essential part of diagnostic process
In all patients with nasal problems....

ann in thrice* \A/itn \c\\Mf^r rf^cniratorx/ XfTtrt Hicpacizi]
ai \u hi li iujc vvilii luvvtri i trsun a lui y licila uiocast:!

QoL TOOLS

Evaluation of the impact of nasal disease
on

* quality of life

* different domains of physical and
mental functioning

* Generic

* Disease-specific

Helpful in clinical practice and clinical trials

NASAL

EXAMINATION

Evaluation of the

* external and endonasal anatomy

* endonasal mucosa and lumen

* Inspection

* Palpation

* Ant. and post,
rhinoscopy

* Nasal endoscopy

* Non-ENT doctors should examine the nose including ant.
rhinoscopy

* A nasal endoscopy is recommended in
chronic rhinologic disease

ALLERGY TEST

Evaluation of the sensitization state,
including the demonstration of the
specific sensitization state

* Skin prick test

* Blood analysis with
allergen-specific IgE

Recommended in all patients with clinical suspicion of
allergic AW disease

NASAL

PROVOCATION

Evaluation of the response of the nasal
mucosa to

* allergens

* aspirin

* occupational agents

Provocation by
inhalation, spray, nasa
drop or discette

Recommended in case of doubt about sensitization

SMELL TEST

Evaluation of the smell capacity

Different tests are
currently available

Recommended in case of severe hyposmia or anosmia

TASTE TEST

Evaluation of taste capacity

Electrogustometry

Recommended in patients with taste dysfunction

NASAL

PATENCY

MEASUREMENTS

Evaluation of a patients' capacity to
breathe through the nose

* PNIF

* Anterior
rhinomanometry

* Acoustic rhinometry

Recommended parameter in clinical trials

Helpful in clinical practise to evaluate the evolution of nasal

patency

NO

measurement

Evaluation of NO levels in nasal cavity

Chemiluminiscence
reaction of expired air

Helpful as screening tool in PCD

NASAL
SAMPLING

Collection of nasal mucosa/cells/
secretions for analysis

* Nasal secretions

* Nasal scraping

* Nasal biopsy

Recommendations:

* nasal sampling in experimental/clinical studies

* nasal secretions for B2 transferrin analysis in suspicion of
CSF leak

* biopsy in case of unilateral/malignant disease

BLOOD AND
ADDITIONAL
TESTS

Evaluation of the sensitization state,
immune system, endocrine system
Evaluation of mucociliary function
Evalution of chloride content in sweat

* Blood test

* MCT, nasal NO, EM,
ciliogenesis in vitro

* Sweat test

Recommended as diagnostic tool in severe rhinitis,
rhinosinusitis and nasal polyp disease with suspicion of
underlying auto-immune, immunologic or ciliary disease

Test-time: 35 min.
Test-retest reliability: not found.
Country: USA
Smell diskettes test

Method: A screening test of olfaction was designed
[135] using 8 diskettes containing different odorants
(coffee, vanilla, smoke, peach, pineapple, rose, coconut,
vinegar). These diskettes (5x6 cm) are widely used in
the perfume and flavour industry as applicators for
odorants. The odorants were used in a high suprathres-
hold concentration. The test was designed as a triple
forced multiple choice test, resulting in a score from 0

to 8 correct answers. The answers were presented on a
questionnaire with illustrations.

Test-time: 5 min.

Test-retest reliability: r = 0.99

Country: Zurich, Switzerland
Odourant confusion matrix

Method: Odorant identification test in which the number
of correct odorant identifications quantifies the level of
olfactory function [136]. The OCM reflects distortions of
sensory perception as errors in identification. Subjects
attempted to identify each of 10 odorant (ammonia, cin-
namon, licorice, mint, mothballs, orange, rose, rubbing

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alcohol, vanilla, vinegar, vex) stimuli (plus a blank known
as a vex) from a list of 10 odorant names, which was visi-
ble at all times. Subjects were not told of the presence of
the vex, and were asked to respond to all stimuli with an
odor name chosen from the list of names. The 11 stimuli
were given to the subject in 11 randomized blocks,
resulting in a total of 121 stimulus presentations [136].

Test-time: 15 min.

Test-retest reliability: not found.

Country: USA
Dutch odour identification test (GITU)

Method: Identification of 18 or 36 odours in jars. Forced
choice either from 4 alternatives or from a list of 24 for
18 odours to identify [137].

Test-time: not found.

Test-retest reliability: not found.

Subject differences:

Country: The Netherlands
YN-odour Identification Test (YN-OIT)

Methods: identification was assessed with a four alterna-
tive-forced-choice task modified from the UPSIT odours
and a yes/no task yielding measures of discrimination
and response bias for the same stimulus material [138].

Test-time: not found

Test-retest: not found

Country: USA
T&T Olfactometer

Methods: The T&T olfactometer is the most commonly
method used in patients suffering from smelling disor-
ders. The T&T olfactometer (Daiichi-Yakuhin, Tokyo,
Japan) consists of five test odorants [139]. Each odorant
was diluted into eight log-step concentration series with
either propylene glycol or liquid paraffin (grade 5 to -2).
The detection threshold is the weakest concentration at
which the stimulus is firstly noticed. The concentration
at which a qualitative sensation is first recognized is
recorded as the recognition threshold.

Test-time: not found

Test-retest: not found

Country: Japan
San Diego Odor Identification Test (SDOIT)
Methods: Eight-item odour blind identification test [140]
that uses common odours typically found in the home
(chocolate, coffee, etc). Odorants were wrapped in gauze
and kept in opaque containers to minimize visual clues.
The inter-stimulus interval was 45 seconds to minimize
adaptation. A picture board with illustrations of the tar-
get items (8) as well as distracters (12) was presented to
aid in identification. The odorants were presented in
random order to the participant

Test-time: not found

Test-retest: r: 0.86

Country: USA

Cross-Cultural Smell Identification Test (CC-SIT)

Methods: 12-item self-administered micro-encapsuled
odour identification test, analogous to the UPSIT that
incorporates multicultural odorant items selected from the
UPSIT that are familiar to most persons from North
America, European, South American, and Asian cultures
[141].

Test-time: <5 min.

Test-retest: r: 0.71

Country: USA, Europe, Asia
Combined olfactory test (COT)

Robson et al. [142] creates the COT developed a screen-
ing test to evaluate the olfaction in adults and children.

Method: Threshold with n-butanol in plastic contain-
ers, and identification of 9 odours in jars with forced
choice with 4 options.

Test-time: not found

Test-retest reliability: not found

Country: UK, New Zealand
Sniff in' -Sticks

Method: Test of nasal chemosensory performance based
on pen-like odour dispensing devices [143]. For evaluation
of odour sensation, the cap was removed by the clinician
for 3 seconds and the pen's tip placed 2 cm from both
nostrils. It comprises three tests of olfactory function,
namely tests for odour threshold (n-butanol by means of a
single staircase), odour discrimination (16 pairs of odor-
ants, triple forced choice), and odour identification
(16 common odorants, multiple forced choice from four
verbal items per test odorant). Criteria for the selection of
odorants were as follows: 1. subjects should be familiar
with all odor-describing items used in the test; 2. odorants
included in the test should be similar with regard to both
intensity and hedonic tone; and 3. the successful identifi-
cation of individual odorants from a list of four descriptors
should be >75% in healthy subjects.
Test-time: 25 min.

Test-retest reliability: r: 0.61, r: 0.54, and r: 0.73 for
threshold, discrimination, and identification respectively.

Country: Germany, USA
Candy smell test (CST)

Method: an easy-to-use, reliable, and fast test of retrona-
sal olfactory performance (23 aromatized sorbitol candies
using a four-alternative with forced-choice procedure)
suitable for the screening of smell function in children
above the age of 6 years and adults [144].

Test-time: 5 minutes

Test-retest reliability: r = 0.75.

Country: Germany.
Alcohol Sniff Test (AST)

Method: In 1997, Davidson and Murphy developed a
screening test to evaluate the olfaction in adults and
children [145]. The AST is a rapidly administered and

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employs odour material readily available in the medical
environment, providing a measure of first cranial nerve
activity. A standard 70% isopropyl alcohol prep pad was
opened such that 0.5 cm of the pad itself was visible.
The alcohol pad was placed beneath the nostrils while
the subject inspired to familiarize with the alcohol
odour. Active sniffing and deep inspiration were dis-
couraged. Then the alcohol pad was placer 30 cm below
the nose and with each inspiration the pad is placed
lcom closer to the nose until the subject detected the
presence of the odour. The distance from the anterior
nostrils to the alcohol was measured in cm. The proce-
dure was repeated five times and the mean distance
defined the threshold.

Test-time: 5 minutes

Test-retest reliability: r = 0.8.

Country: USA
Culturally Adjusted University of Pennsylvania Smell
Identification Test (CA-UPSIT)

Method: Ahlskog et al. developed a culturally adjusted
olfactory test battery, derived from the original UPSIT
for clinical use on the Chamorro inhabitants of Guam, a
western Pacific island [146]. Identification of 20 microen-
capsulated odours with the "scratch and sniff technique.
Each of the 20 odours has four response alternatives.
Target odours included: smoke, lilac, lemon, bubble gum,
motor oil, banana, leather, coconut, onion, gasoline, pea-
nut, dill pickle, lime, watermelon, grass, soap, cherry,
strawberry, root beer, and mint.

Test-time: not found

Test-retest reliability: not found.

Country: USA
Kremer et al [147]

Method: Olfactory test using spray bottles. The atomizer
bottles were made of glass and contained 12.5 ml (10 g)
of fluid. A special administration valve limited the
amount of solution set free with each application to
exactly 2 mg. The even distribution of the expelled solu-
tion was assured by the extremely fine atomization pro-
duced. The average size of the aerosol was 40 um. For
hygienic reasons a replaceable valve was used. To imple-
ment the olfactory test using spray bottles the patient
was required to hold the atomizer 5 cm before an opened
mouth. The spray was administered during inspiration,
and afterwards the patient was asked to exhale through
the nose, keeping the mouth closed. Alternatively, the
solution colud be sprayed into the lid of the bottleand
then be sniffed. Between separate applications the patient
was given a rest period of at least 30 seconds. The sub-
stances in the olfactory spray test were: rose, cinnamon,
banana, pine essence, tangerine, and peppermint. The
spray test was shown to be easily performed and was sui-
table as a screening test, with a sensitivity of 88% and a
specificity of 100%.

Test-time: 4 minutes

Test-retest reliability: not found

Country: Germany, The Netherlands
Scandinavian Odour-Identification Test (SOIT)
Method: Nordin et al. [148] developed this olfactory test
to address the need for a culturally valid odour-identifica-
tion test for clinical use on the Scandinavian population
that has good ability to generalize performance to olfac-
tory status, assess olfactory and trigeminal function sepa-
rately with a good sensitivity and specificity. 16 odours
('pine needle, peppermint, juniper berry, violet, orange,
cinnamon, lilac, apple, lemon, tar, anise, vanilla, bitter
almond, clove, ammonia) to assess both cranial nerves.
The stimulus order was randomize for each participant
(>600). The liquid odorant was injected into a tampon
filled to saturation and placed in an opaque, 80 ml glass
jar. For each stimulus the participant was provided with a
written list of four response alternatives from which to
choose the most appropriate item for identification. The
stimuli were presented birhinally, 5 cm under the nose,
for as long as required to accomplish the task.

Test-time: 15 minutes

Test-retest reliability: r = 0.79.

Country: Sweden, Finland
Pocket Smell Test [56]

Method: A screening measure of odour identification
derived from the University of Pennsylvania Smell Identi-
fication Test (UPSIT) with identification of 3 microen-
capsulated odours with the "scratch and sniff technique.
Each of the three PST tasks contains four response alter-
natives [149]. Target odours included: smoke, lilac, and
lemon. After releasing the odour, the examiner read the
four response alternatives continuously until the patient
responded. Patients were encouraged to guess if they
were unsure. Nostrils were not tested separately.

Sample size: 140

Country: USA
Eloit and Trotier Olfactory Test

Methods: computed-assisted olfactory test to measure
thresholds, detection, and identification using 5 odours:
phenyl-ethyl-alcohol (PEA; flowers, rose, jasmine), cyclo-
tene (CYC; caramel, cake), isovaleric acid (IVA; fruits,
apricot, peach), undecalactone (UND; cowshed, slurry),
and skatole (SKA; faecal). These chemically stable sub-
stances in bottles evoke different odour notes. A software
was developed to assist in the procedure of the experi-
ment. At the beginning, participants get accustomed with
the 5 odours at the highest concentration and learned to
name them. Every odour was divided in 7 different des-
cending concentrations. For each bottle, the subject was
asked to decide whether it contained an odorant and, if
so, which odorant was present. For each odorant, the
detection level was taken as the highest concentration
not perceived plus one. The identification level was taken

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as the smallest concentration correctly identified in a ser-
ies of correct identification beginning with the highest
concentration [150].

Test-time: not found

Test-retest: not found

Country: France
Ramdon Test

Method: a labelling of 16 concentrations of two odor-
ants (citrus, rose) randomly presented for thresholds,
discrimination, and identification [151]. Subjects were
blindfolded to prevent visual identification of the odour-
containing pens.

Test-time: 10 minutes

Test-retest reliability: r = 0.71.

Country: Germany
Four-minute odour identification test

Method: Screening test on the basis of the odour identifi-
cation test as used in the "Sniffin' Sticks" olfactory test
[152]. Identification of 12 microencapsulated odours in
pens. For odour presentation the cap is removed by the
experimenter for approximately 3 seconds and the pen's
tip is placed approximately 2 cm in front of both nostrils.
Identification of individual odorants was performed from a
list of 4 descriptors each. Target odours included: cinna-
mon, banana, lemon, licorice, pineapple, coffe, cloves, rose,
leather, fish, orange, and peppermint. Nostrils can be
tested separately.

Test-time: 4 minutes

Test-retest reliability: r = 0.78.

Country: Germany
Barcelona Smell Test (BAST-24)

Method: Olfactory test addressed to the need for a cultu-
rally valid odour-identification test for clinical use on the
Spanish population and in general for the Mediterranean
countries. 24 odours, 20 odours (banana, gasoline, lemon,
rose, onion, smoked, anise, coconut, vanilla, melon, man-
darin, bitter almond, pineapple, cheese, strawberry, mush-
room, eucalyptol, clove, turpentine, and peach) to assess
the 1st cranial nerve and 4 odours (vinegar, formol, mus-
tard, ammonia) to assess the 5th cranial nerve. Hermetic
containers were designed to contain the different odorants
in a semi-solid state. BAST-24 scores smell detection,
identification, and forced choice. Nostrils can be tested
separately, smell identification was scored slightly higher
in the left than in the right nostril for both cranial nerve.
BAST-24 was found to be a valid, reliable, and reproduci-
ble test [153].

Test-time: 20 minutes.

Test-retest reliability:

Country: Spain
Nez du Vin smell test

Six odours initially derived from a kit used to educate
wine tasters presented on paper strips with a forced
choice between 4 possibilities.

Time: 2 minutes

Test retest -correlation with UPSIT: r = 0.79, p <

0. 001
Country:UK

Nez du Vin smell test

Six odours initially derived from a kit used to educate
wine tasters presented on paper strips with a forced
choice between 4 possibilities [154]. Test-time: 2 min.
Test retest -correlation with UPSIT: r = 0.79, p < 0.001.
Country:UK

Consent

Consent for publication of photos was obtained from all
pictured patients or their relatives.

Abbreviations

AR: Allergic rhinitis; ASNC: Allergen-specific nasal challenge test; CF: Cystic
fibrosis; CRS: Chronic rhinosinusitis; CT scan: Computerized Tomography
scan; MRI: Magnetic resonance imaging; NL: Nasal lavage; NO: Nitric oxicde;
NP: Nasal polyps; PCD: Primay ciliary dyskinesia; PNIF: Peak nasal inspiratory
flow.

Author details

1 Royal National Throat, Nose and Ear Institute, London, UK. 2 University
Hospitals Leuven, Belgium. 3 University Hospital Barcelona, Spain. 4 University
Hospital Ghent, Belgium. 5 University Hospital Amsterdam, The Netherlands.
6 University Hospital Rotterdam, The Netherlands. 'University Hospital Zagreb,
Croatia. 8 University Hospital of Genoa, Italy. 'Center for Applied Genomics,
Philadelphia, USA.

Authors' contributions

History of patient by GS; nasal clinical examination by PH; allergy tests and
nasal provocation tests by GP; assessing the senses of smell and taste by JM,
JG and IA; microbiology by LK; blood tests by GS; imaging in rhinology by
LK and VL; evaluation of nasal patency, nasal peak flow, rhinomanometry,
acoustic rhinometry by PH; quality of life assessment in rhinosinusitis, patient
reported outcomes, rhinitis control tests by RGvW; nasal air sampling, NO
measurement by GS; nasal cellular sampling, lavages, cytology, biopsies by
PG and CB; evaluation of mucociliary transport by PH; diagnosis of
occupational rhinitis by ET; future needs in clinical and research tools in
rhinology by WF and CvD; concluding remarks and recommendations by GS
and PH. All authors read and approved the final manuscript.

Competing interests

All authors declare they have no competing interests.

Received: 12 May 2011 Accepted: 10 June 201 1 Published: 10 June 2011

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doi:10.1 186/2045-7022-1-2

Cite this article as: Scadding et al:. Diagnostic tools in Rhinology EAACI
position paper. Clinical and Translational Allergy 201 1 1:2.

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